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Abraham, Soman Ninan

Overview:

The Abraham laboratory is interested in developing innovative approaches for curbing microbial infections through the study of the molecular interactions occurring between pathogenic bacteria and prominent immune and epithelial cells. We believe that there is a significant amount of crosstalk occurring between bacteria and host cells during infection and that the outcome of this interaction dictates both how quickly the infection is cleared and the severity of the pathology associated with the infection. We also believe that through deciphering this crosstalk we should be able to selectively promote certain beneficial interactions while abrogating the harmful ones.


There are two major research areas being pursued in this laboratory. The first involves elucidating the role of mast cells in modulating immune responses to microbes.  Our studies have revealed that mast cells play a key sentinel role and upon bacterial or viral infection, modulate both innate and adaptive immune responses through the release of immunomodulatory molecules borne in granules. Our current investigations are centered on elucidating the molecular and cellular aspects of how mast cells mediate their immunomodulatory role. We are also examining several mast cell-targeted strategies to boost immunity to infections as well as reduce any pathological consequences of infection.


The second area of research investigates cross-talk between distinct infectious agents such as Uropathogenic E. coli, Salmonella typhimurium and Yersinia pestis and the immune system. We have recognized that different pathogens possess distinct mechanisms to evade or coopt one or more immune cells to establish infection. We have also unraveled novel intracellular innate host defense activities including expulsion of whole bacteria from infected epithelial cells, a feat mediated by immune recognition molecules and the cellular trafficking system.


Cumulatively, our studies should facilitate the design of innovative strategies to combat pathogens that selectively potentiate the host’s immune response without evoking some of its harmful side effects.


Positions:

Professor in Pathology

Pathology
School of Medicine

Professor in Immunology

Immunology
School of Medicine

Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1976

B.S. — Ahmadu Bello University (Nigeria)

M.S. 1978

M.S. — Ahmadu Bello University (Nigeria)

Ph.D. 1981

Ph.D. — Newcastle University

Postdoctoral Fellowship

University of Tennessee at Knoxville

Assistant Professor, Medicine

University of Tennessee at Knoxville

Assistant Professor Of Pathology, Microbiology And Immunology

University of Tennessee at Knoxville

Associate Clinical Director, Microbiology/Serology

Washington University

Assistant Professor, Molecular Microbiology

Washington University

Clinical Director, Serology

Washington University

News:

Grants:

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

Interdisciplinary Training Program in Lung Disease

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 2009
End Date
March 31, 2020

IL-27 in skin host defense and regeneration

Administered By
Dermatology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 15, 2017
End Date
July 31, 2019

Basic Immunology Training Program

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2002
End Date
June 30, 2019

Duke KURe Program

Administered By
Obstetrics and Gynecology, Urogynecology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 01, 2013
End Date
July 31, 2018

Understanding the Mechanism of Mucosal Immunotherapy

Administered By
Pathology
AwardedBy
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
August 01, 2012
End Date
July 31, 2018

Platelets as regulators of inflammation and tissue injury after cardiac surgery

Administered By
Anesthesiology, Cardiothoracic
AwardedBy
American Heart Association
Role
Significant Contributor
Start Date
July 01, 2015
End Date
June 30, 2018

Immune mediated exocytosis of intravesicular UPEC from bladder cells

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 07, 2014
End Date
March 31, 2018

Overcoming Immunosenescence by Nanoparticle-Mediated Activation

Administered By
Pathology
AwardedBy
Columbia University
Role
Principal Investigator
Start Date
February 01, 2017
End Date
January 31, 2018

Adjuvant Discovery Program (Option #1)

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 2014
End Date
September 29, 2017

Platelet/Mast Cell Interactions as Determinants of End-Organ Injury in Cardiac Surgery

Administered By
Anesthesiology, Cardiothoracic
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 14, 2015
End Date
August 31, 2017

Enhancing dendritic cell migration to drive potent anti-tumor immune responses

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2013
End Date
June 30, 2017

Mucosal vaccination to protect against HIV-1 infection at mucosal sites

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 01, 2012
End Date
June 30, 2017

Mast Cells in Dengue Pathology and Prevention

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2013
End Date
May 31, 2017

Adjuvant Discovery Program

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 2014
End Date
April 04, 2017

Institutional Training Grant in Pediatric Infectious Disease

Administered By
Pediatrics, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 21, 2011
End Date
December 31, 2016

The role of SP-A in Mp-induced exacerbations during allergic airway disease

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
August 01, 2014
End Date
February 27, 2015

Mechanism of Bacterial Expulsion from Infected Bladder Cells.

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2012
End Date
August 31, 2014

Overcoming Immunosenescence by Nanoparticle-Mediated Activation

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
February 01, 2012
End Date
August 31, 2014

The role of SP-A in Mp-induced exacerbations during allergic airway disease.

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Advisor
Start Date
September 01, 2012
End Date
July 31, 2014

Development of Efficacious and Stable Nasal Vaccine Formulations

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
July 01, 2009
End Date
June 30, 2014

Targeting EGFRvIII in Brain Tumors with Bispecific Antibodies

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
May 01, 2013
End Date
April 30, 2014

Nasal adjuvant to enhance anti-cocaine vaccines

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 2011
End Date
January 31, 2013

Enterotoxin targeting and delivery mechanisms

Administered By
Biochemistry
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
June 15, 2006
End Date
May 31, 2012

Modulation of Bladder cAMP to combat UTI's

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 15, 2007
End Date
April 30, 2012

Caveolae Mediated Bacterial Uptake in the Urinary Tract

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2001
End Date
November 30, 2011

Role Of Surfactant In Innate and Adaptive Immunity

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
July 01, 2001
End Date
September 30, 2011

Development of Efficacious Vaccine Against UTI's

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2008
End Date
March 31, 2011

Small cationic antimicrobial peptides: activators of innate & adaptive immunity

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 25, 2008
End Date
August 31, 2010

Ligand Receptor Interactions in UTIs

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 1976
End Date
June 30, 2010

Mast Cells and IBD Pathogenesis

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 01, 2006
End Date
July 31, 2009

Pseudomonas invasion and the role of caveolin-2

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 29, 2006
End Date
June 30, 2009

Duke PREP: Minority Recruitment into Biomedical Sciences

Administered By
Biochemistry
AwardedBy
National Institutes of Health
Role
Advisor
Start Date
August 01, 2003
End Date
July 31, 2008

Mast Cell Activator as Adjuvant for Biodefense Vaccines

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
May 01, 2005
End Date
April 30, 2007

Proteome Mining in Caveolae of the Bladder Epithelium

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2004
End Date
March 31, 2007

Detection of in vivo ETEC vesicle production

Administered By
Biochemistry
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
March 01, 2003
End Date
February 28, 2006

Mast Cells in Pulmonary Inflammation

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1998
End Date
March 31, 2001
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Awards:

AAAS Fellows. American Association for the Advancement of Science, The.

Type
National
Awarded By
American Association for the Advancement of Science, The
Date
January 01, 2012

Publications:

IL-27 Facilitates Skin Wound Healing through Induction of Epidermal Proliferation and Host Defense.

Skin wound repair requires a coordinated program of epithelial cell proliferation and differentiation as well as resistance to invading microbes. However, the factors that trigger epithelial cell proliferation in this inflammatory process are incompletely understood. In this study, we demonstrate that IL-27 is rapidly and transiently produced by CD301b+ cells in the skin after injury. The functional role of IL-27 and CD301b+ cells is demonstrated by the finding that CD301b-depleted mice exhibit delayed wound closure in vivo, which could be rescued by topical IL-27 treatment. Furthermore, genetic ablation of the IL-27 receptor (Il27Ra-/-) attenuates wound healing, suggesting an essential role for IL-27 signaling in skin regeneration in vivo. Mechanistically, IL-27 feeds back on keratinocytes to stimulate cell proliferation and re-epithelialization in the skin, whereas IL-27 leads to suppression of keratinocyte terminal differentiation. Finally, we identify that IL-27 potently increases expression of the antiviral oligoadenylate synthetase 2, but does not affect expression of antibacterial human beta defensin 2 or regenerating islet-derived protein 3-alpha. Together, our data suggest a previously unrecognized role for IL-27 in regulating epithelial cell proliferation and antiviral host defense during the normal wound healing response.

Authors
Yang, B; Suwanpradid, J; Sanchez-Lagunes, R; Choi, HW; Hoang, P; Wang, D; Abraham, SN; MacLeod, AS
MLA Citation
Yang, B, Suwanpradid, J, Sanchez-Lagunes, R, Choi, HW, Hoang, P, Wang, D, Abraham, SN, and MacLeod, AS. "IL-27 Facilitates Skin Wound Healing through Induction of Epidermal Proliferation and Host Defense." May 2017.
PMID
28132857
Source
epmc
Published In
Journal of Investigative Dermatology
Volume
137
Issue
5
Publish Date
2017
Start Page
1166
End Page
1175
DOI
10.1016/j.jid.2017.01.010

The multiple antibacterial activities of the bladder epithelium.

The urinary tract is subject to frequent challenges from the gut microflora. Indeed, up to 40% of women will experience at least one urinary tract infection (UTI) during their lifetime. Uropathogenic Escherichia coli (UPEC) contribute to an overwhelming majority of these cases and they typically initiate UTIs by invading the superficial epithelium that lines the bladder lumen. In addition to serving as an effective barrier to noxious agents found in urine, bladder epithelial cells (BECs) play a key physiological role in regulating bladder volume to accommodate urine flow. UPEC appear to coopt this latter property to circumvent this normally impregnable epithelial barrier. However, in spite of this shortcoming, recent studies suggest that BECs possess several immune mechanisms to combat bacterial invasion including expulsion of invading bacteria back into the bladder lumen following infection. These antibacterial activities of BECs are triggered and coordinated by sensory molecules located on the epithelial cell membrane and within the cells. Although, they are the primary targets of microbial attack, BECs appear to be equipped with a diverse repertoire of defense schemes to fend off many of these microbial challenges.

Authors
Wu, J; Miao, Y; Abraham, SN
MLA Citation
Wu, J, Miao, Y, and Abraham, SN. "The multiple antibacterial activities of the bladder epithelium." Annals of translational medicine 5.2 (January 2017): 35-. (Review)
PMID
28217700
Source
epmc
Published In
Annals of translational medicine
Volume
5
Issue
2
Publish Date
2017
Start Page
35
DOI
10.21037/atm.2016.12.71

Loss of Bladder Epithelium Induced by Cytolytic Mast Cell Granules.

Programmed death and shedding of epithelial cells is a powerful defense mechanism to reduce bacterial burden during infection but this activity cannot be indiscriminate because of the critical barrier function of the epithelium. We report that during cystitis, shedding of infected bladder epithelial cells (BECs) was preceded by the recruitment of mast cells (MCs) directly underneath the superficial epithelium where they docked and extruded their granules. MCs were responding to interleukin-1β (IL-1β) secreted by BECs after inflammasome and caspase-1 signaling. Upon uptake of granule-associated chymase (mouse MC protease 4 [mMCPT4]), BECs underwent caspase-1-associated cytolysis and exfoliation. Thus, infected epithelial cells require a specific cue for cytolysis from recruited sentinel inflammatory cells before shedding.

Authors
Choi, HW; Bowen, SE; Miao, Y; Chan, CY; Miao, EA; Abrink, M; Moeser, AJ; Abraham, SN
MLA Citation
Choi, HW, Bowen, SE, Miao, Y, Chan, CY, Miao, EA, Abrink, M, Moeser, AJ, and Abraham, SN. "Loss of Bladder Epithelium Induced by Cytolytic Mast Cell Granules." Immunity 45.6 (December 2016): 1258-1269.
PMID
27939674
Source
epmc
Published In
Immunity
Volume
45
Issue
6
Publish Date
2016
Start Page
1258
End Page
1269
DOI
10.1016/j.immuni.2016.11.003

Innate Immune Responses to Bladder Infection.

Urinary tract infections are one of the most frequent bacterial infections of mankind. In spite of this frequency, the study of the immune system in the urinary tract has not attracted much attention. This could, in part, be attributable to the widespread use of antibiotics and similar antimicrobial agents, which for many decades have been both highly effective and relatively inexpensive to administer. In light of the emergence of multidrug-resistant bacteria among urinary tract infection isolates, interest in understanding the immune system in the urinary tract has grown. Several recent studies have revealed the existence of a powerful and highly coordinated innate immune system in the urinary tract designed to rapidly clear infecting pathogens; however, it also evokes harmful side effects.

Authors
Hayes, BW; Abraham, SN
MLA Citation
Hayes, BW, and Abraham, SN. "Innate Immune Responses to Bladder Infection." Microbiology spectrum 4.6 (December 2016). (Review)
PMID
28084200
Source
epmc
Published In
Microbiology spectrum
Volume
4
Issue
6
Publish Date
2016
DOI
10.1128/microbiolspec.uti-0024-2016

Mast cell desensitization inhibits calcium flux and aberrantly remodels actin.

Rush desensitization (DS) is a widely used and effective clinical strategy for the rapid inhibition of IgE-mediated anaphylactic responses. However, the cellular targets and underlying mechanisms behind this process remain unclear. Recent studies have implicated mast cells (MCs) as the primary target cells for DS. Here, we developed a murine model of passive anaphylaxis with demonstrated MC involvement and an in vitro assay to evaluate the effect of DS on MCs. In contrast with previous reports, we determined that functional IgE remains on the cell surface of desensitized MCs following DS. Despite notable reductions in MC degranulation following DS, the high-affinity IgE receptor FcεRI was still capable of transducing signals in desensitized MCs. Additionally, we found that displacement of the actin cytoskeleton and its continued association with FcεRI impede the capacity of desensitized MCs to evoke the calcium response that is essential for MC degranulation. Together, these findings suggest that reduced degranulation responses in desensitized MCs arise from aberrant actin remodeling, providing insights that may lead to improvement of DS treatments for anaphylactic responses.

Authors
Ang, WXG; Church, AM; Kulis, M; Choi, HW; Burks, AW; Abraham, SN
MLA Citation
Ang, WXG, Church, AM, Kulis, M, Choi, HW, Burks, AW, and Abraham, SN. "Mast cell desensitization inhibits calcium flux and aberrantly remodels actin." The Journal of clinical investigation 126.11 (November 2016): 4103-4118.
PMID
27669462
Source
epmc
Published In
Journal of Clinical Investigation
Volume
126
Issue
11
Publish Date
2016
Start Page
4103
End Page
4118
DOI
10.1172/jci87492

How mast cells make decisions.

Mast cells (MCs) are present in various tissues and are responsible for initiating many of the early inflammatory responses to extrinsic challenges. Recent studies have demonstrated that MCs can tailor their responses, depending on the stimulus encountered and the tissue in which they are stimulated. In this issue of the JCI, Gaudenzio and colleagues examine the mechanistic differences between MC responses observed after engagement of Fcε receptor I and those seen after MC stimulation via the recently identified G protein-coupled receptor MRGPRX2. By showing that discrete cellular activation patterns affect the phenotype of the MC response in vivo and in vitro, the authors provide important information about how MCs differentially process various stimuli into distinct degranulation programs.

Authors
Karhausen, J; Abraham, SN
MLA Citation
Karhausen, J, and Abraham, SN. "How mast cells make decisions." The Journal of clinical investigation 126.10 (October 2016): 3735-3738.
PMID
27643441
Source
epmc
Published In
Journal of Clinical Investigation
Volume
126
Issue
10
Publish Date
2016
Start Page
3735
End Page
3738
DOI
10.1172/jci90361

Cross-reactive antibodies enhance live attenuated virus infection for increased immunogenicity.

Vaccination has achieved remarkable successes in the control of childhood viral diseases. To control emerging infections, however, vaccines will need to be delivered to older individuals who, unlike infants, probably have had prior infection or vaccination with related viruses and thus have cross-reactive antibodies against the vaccines. Whether and how these cross-reactive antibodies impact live attenuated vaccination efficacy is unclear. Using an open-label randomized trial design, we show that subjects with a specific range of cross-reactive antibody titres from a prior inactivated Japanese encephalitis vaccination enhanced yellow fever (YF) immunogenicity upon YF vaccination. Enhancing titres of cross-reactive antibodies prolonged YF vaccine viraemia, provoked greater pro-inflammatory responses, and induced adhesion molecules intrinsic to the activating Fc-receptor signalling pathway, namely immune semaphorins, facilitating immune cell interactions and trafficking. Our findings clinically demonstrate antibody-enhanced infection and suggest that vaccine efficacy could be improved by exploiting cross-reactive antibodies.

Authors
Chan, KR; Wang, X; Saron, WAA; Gan, ES; Tan, HC; Mok, DZL; Zhang, SL-X; Lee, YH; Liang, C; Wijaya, L; Ghosh, S; Cheung, YB; Tannenbaum, SR; Abraham, SN; St John, AL; Low, JGH; Ooi, EE
MLA Citation
Chan, KR, Wang, X, Saron, WAA, Gan, ES, Tan, HC, Mok, DZL, Zhang, SL-X, Lee, YH, Liang, C, Wijaya, L, Ghosh, S, Cheung, YB, Tannenbaum, SR, Abraham, SN, St John, AL, Low, JGH, and Ooi, EE. "Cross-reactive antibodies enhance live attenuated virus infection for increased immunogenicity." Nature microbiology (September 19, 2016): 16164-.
PMID
27642668
Source
epmc
Published In
Nature microbiology
Publish Date
2016
Start Page
16164
DOI
10.1038/nmicrobiol.2016.164

Ubiquitination of Innate Immune Regulator TRAF3 Orchestrates Expulsion of Intracellular Bacteria by Exocyst Complex.

Although the intracellular trafficking system is integral to most physiologic activities, its role in mediating immune responses to infection has remained elusive. Here, we report that infected bladder epithelial cells (BECs) mobilized the exocyst complex, a powerful exporter of subcellular vesicles, to rapidly expel intracellular bacteria back for clearance. Toll-like receptor (TLR) 4 signals emanating from bacteria-containing vesicles (BCVs) were found to trigger K33-linked polyubiquitination of TRAF3 at Lys168, which was then detected by RalGDS, a guanine nucleotide exchange factor (GEF) that precipitated the assembly of the exocyst complex. Although this distinct modification of TRAF3 served to connect innate immune signaling to the cellular trafficking apparatus, it crucially ensured temporal and spatial accuracy in determining which among the many subcellular vesicles was recognized and selected for expulsion in response to innate immune signaling.

Authors
Miao, Y; Wu, J; Abraham, SN
MLA Citation
Miao, Y, Wu, J, and Abraham, SN. "Ubiquitination of Innate Immune Regulator TRAF3 Orchestrates Expulsion of Intracellular Bacteria by Exocyst Complex." Immunity 45.1 (July 2016): 94-105.
PMID
27438768
Source
epmc
Published In
Immunity
Volume
45
Issue
1
Publish Date
2016
Start Page
94
End Page
105
DOI
10.1016/j.immuni.2016.06.023

Cytokine expression by invariant natural killer T cells is tightly regulated throughout development and settings of type-2 inflammation.

Invariant natural killer T (iNKT) cells produce cytokines interleukin-4 (IL-4) and IL-13 during type-2 inflammatory responses. However, the nature in which iNKT cells acquire type-2 cytokine competency and the precise contribution of iNKT cell-derived IL-4 and IL-13 in vivo remains unclear. Using IL-13-reporter mice to fate-map cytokine-expressing cells in vivo, this study reveals that thymic iNKT cells express IL-13 early during development, and this IL-13-expressing intermediate gives rise to mature iNKT1, iNKT2, and iNKT17 subsets. IL-4 and IL-13 reporter mice also reveal that effector iNKT2 cells produce IL-4 but little IL-13 in settings of type-2 inflammation. The preferential production of IL-4 over IL-13 in iNKT2 cells results in part from their reduced GATA-3 expression. In summary, this work helps integrate current models of iNKT cell development, and further establishes non-coordinate production of IL-4 and IL-13 as the predominant pattern of type-2 cytokine expression among innate cells in vivo.

Authors
O'Brien, TF; Bao, K; Dell'Aringa, M; Ang, WXG; Abraham, S; Reinhardt, RL
MLA Citation
O'Brien, TF, Bao, K, Dell'Aringa, M, Ang, WXG, Abraham, S, and Reinhardt, RL. "Cytokine expression by invariant natural killer T cells is tightly regulated throughout development and settings of type-2 inflammation." Mucosal immunology 9.3 (May 2016): 597-609.
PMID
26349658
Source
epmc
Published In
Mucosal immunology
Volume
9
Issue
3
Publish Date
2016
Start Page
597
End Page
609
DOI
10.1038/mi.2015.78

Why Serological Responses during Cystitis are Limited.

The high frequency of urinary tract infections (UTIs), some of which appear to be endogenous relapses rather than reinfections by new isolates, point to defects in the host's memory immune response. It has been known for many decades that, whereas kidney infections evoked an antibody response to the infecting bacteria, infections limited to the bladder failed to do so. We have identified the existence of a broadly immunosuppressive transcriptional program associated with the bladder, but not the kidneys, during infection of the urinary tract that is dependent on bladder mast cells. This involves the localized secretion of IL-10 and results in the suppression of humoral immune responses in the bladder. Mast cell-mediated immune suppression could suggest a role for these cells in critically balancing the needs to clear infections with the imperative to prevent harmful immune reactions in the host.

Authors
Choi, HW; Abraham, SN
MLA Citation
Choi, HW, and Abraham, SN. "Why Serological Responses during Cystitis are Limited." Pathogens (Basel, Switzerland) 5.1 (February 14, 2016). (Review)
Website
http://hdl.handle.net/10161/12469
PMID
26907352
Source
epmc
Published In
Pathogens
Volume
5
Issue
1
Publish Date
2016
DOI
10.3390/pathogens5010019

Correction notice for TNF-R on mast cells regulate airway responses to Mycoplasma pneumoniae.

Authors
Hsia, BJ; Ledford, JG; Potts-Kant, EN; Nikam, VS; Lugogo, NL; Foster, WM; Kraft, M; Abraham, SN; Wright, JR
MLA Citation
Hsia, BJ, Ledford, JG, Potts-Kant, EN, Nikam, VS, Lugogo, NL, Foster, WM, Kraft, M, Abraham, SN, and Wright, JR. "Correction notice for TNF-R on mast cells regulate airway responses to Mycoplasma pneumoniae." The Journal of allergy and clinical immunology 137.1 (January 2016): 336-.
PMID
26611673
Source
epmc
Published In
Journal of Allergy and Clinical Immunology
Volume
137
Issue
1
Publish Date
2016
Start Page
336
DOI
10.1016/j.jaci.2015.09.049

Ubiquitination of TRAF3 Orchestrates Expulsion of Intracellular Bacteria by Exocyst Complex

Authors
Abraham, SN; Miao Y, WJ
MLA Citation
Abraham, SN, and Miao Y, WJ. "Ubiquitination of TRAF3 Orchestrates Expulsion of Intracellular Bacteria by Exocyst Complex (Accepted)." Immunity (2016).
Source
manual
Published In
Immunity
Publish Date
2016

The nature of immune responses to urinary tract infections.

The urinary tract is constantly exposed to microorganisms that inhabit the gastrointestinal tract, but generally the urinary tract resists infection by gut microorganisms. This resistance to infection is mainly ascribed to the versatility of the innate immune defences in the urinary tract, as the adaptive immune responses are limited particularly when only the lower urinary tract is infected. In recent years, as the strengths and weaknesses of the immune system of the urinary tract have emerged and as the virulence attributes of uropathogens are recognized, several potentially effective and unconventional strategies to contain or prevent urinary tract infections have emerged.

Authors
Abraham, SN; Miao, Y
MLA Citation
Abraham, SN, and Miao, Y. "The nature of immune responses to urinary tract infections." Nature reviews. Immunology 15.10 (October 2015): 655-663. (Review)
PMID
26388331
Source
epmc
Published In
Nature Reviews Immunology
Volume
15
Issue
10
Publish Date
2015
Start Page
655
End Page
663
DOI
10.1038/nri3887

Complete Genome Sequence of Uropathogenic Escherichia coli Strain CI5

Authors
Mehershahi, KS; Abraham, SN; Chen, SL
MLA Citation
Mehershahi, KS, Abraham, SN, and Chen, SL. "Complete Genome Sequence of Uropathogenic Escherichia coli Strain CI5." Genome Announcements 3.3 (June 25, 2015): e00558-15-e00558-15.
Source
crossref
Published In
Genome Announcements
Volume
3
Issue
3
Publish Date
2015
Start Page
e00558-15
End Page
e00558-15
DOI
10.1128/genomeA.00558-15

A TRP Channel Senses Lysosome Neutralization by Pathogens to Trigger Their Expulsion.

Vertebrate cells have evolved elaborate cell-autonomous defense programs to monitor subcellular compartments for infection and to evoke counter-responses. These programs are activated by pathogen-associated pattern molecules and by various strategies intracellular pathogens employ to alter cellular microenvironments. Here, we show that, when uropathogenic E. coli (UPEC) infect bladder epithelial cells (BECs), they are targeted by autophagy but avoid degradation because of their capacity to neutralize lysosomal pH. This change is detected by mucolipin TRP channel 3 (TRPML3), a transient receptor potential cation channel localized to lysosomes. TRPML3 activation then spontaneously initiates lysosome exocytosis, resulting in expulsion of exosome-encased bacteria. These studies reveal a cellular default system for lysosome homeostasis that has been co-opted by the autonomous defense program to clear recalcitrant pathogens.

Authors
Miao, Y; Li, G; Zhang, X; Xu, H; Abraham, SN
MLA Citation
Miao, Y, Li, G, Zhang, X, Xu, H, and Abraham, SN. "A TRP Channel Senses Lysosome Neutralization by Pathogens to Trigger Their Expulsion." Cell 161.6 (June 2015): 1306-1319.
PMID
26027738
Source
epmc
Published In
Cell
Volume
161
Issue
6
Publish Date
2015
Start Page
1306
End Page
1319
DOI
10.1016/j.cell.2015.05.009

Basophil Hyporesponsiveness Following Six Months of Peanut Oral Immunotherapy (OIT) Is Associated with Suppression of Syk Phosphorylation

Authors
Jr, KMD; Burk, C; Yue, X; Zhang, H; Steele, PH; Hamilton, DK; Beavers, A; Wright, BL; Abraham, SN; Vickery, BP; Burks, AW
MLA Citation
Jr, KMD, Burk, C, Yue, X, Zhang, H, Steele, PH, Hamilton, DK, Beavers, A, Wright, BL, Abraham, SN, Vickery, BP, and Burks, AW. "Basophil Hyporesponsiveness Following Six Months of Peanut Oral Immunotherapy (OIT) Is Associated with Suppression of Syk Phosphorylation." February 2015.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
135
Issue
2
Publish Date
2015
Start Page
AB24
End Page
AB24

Mast cell mediator responses and their suppression by pathogenic and commensal microorganisms

© 2014 Elsevier Ltd. Mast cells (MCs) are selectively found at the host environment interface and are capable of secreting a wide array of pharmacologically active mediators, many of which are prepackaged in granules. Over the past two decades, it has become clear that these cells have the capacity to recognize a range of infectious agents allowing them to play a key role in initiating and modulating early immune responses to infectious agents. However, a number of pathogenic and commensal microbes appear to have evolved distinct mechanisms to suppress MC mediator release to avoid elimination in the host. Understanding how these microbes suppress MC functions may have significant therapeutic value to relieve inflammatory disorders mediated by MCs.

Authors
Choi, HW; Abraham, SN
MLA Citation
Choi, HW, and Abraham, SN. "Mast cell mediator responses and their suppression by pathogenic and commensal microorganisms." Molecular Immunology 63.1 (January 1, 2015): 74-79. (Review)
Source
scopus
Published In
Molecular Immunology
Volume
63
Issue
1
Publish Date
2015
Start Page
74
End Page
79
DOI
10.1016/j.molimm.2014.02.006

Mast cell mediator responses and their suppression by pathogenic and commensal microorganisms.

Mast cells (MCs) are selectively found at the host environment interface and are capable of secreting a wide array of pharmacologically active mediators, many of which are prepackaged in granules. Over the past two decades, it has become clear that these cells have the capacity to recognize a range of infectious agents allowing them to play a key role in initiating and modulating early immune responses to infectious agents. However, a number of pathogenic and commensal microbes appear to have evolved distinct mechanisms to suppress MC mediator release to avoid elimination in the host. Understanding how these microbes suppress MC functions may have significant therapeutic value to relieve inflammatory disorders mediated by MCs.

Authors
Choi, HW; Abraham, SN
MLA Citation
Choi, HW, and Abraham, SN. "Mast cell mediator responses and their suppression by pathogenic and commensal microorganisms." Molecular immunology 63.1 (January 2015): 74-79. (Review)
PMID
24636146
Source
epmc
Published In
Molecular Immunology
Volume
63
Issue
1
Publish Date
2015
Start Page
74
End Page
79
DOI
10.1016/j.molimm.2014.02.006

Adhesion and Colonization

© 2015, 2002 Elsevier Ltd. All rights reserved. The binding of bacterial adhesins to host receptors is a dynamic process occurring in several steps, which involve complex bacteria-host cell interaction. Initial weak physical interactions lead to more specific adhesion mechanisms that may be shared by several organisms, but eventually to species-specific adhesins that may elicit both bacterial and host factors leading to host cell damage, induction of inflammation and disease. Species-specific fimbrial adhesins may be viewed as direct mediators of bidirectional signalling between bacteria and host cells. Understanding of this process has been highly informative for the design of novel strategies to modulate these signalling pathways and to curb bacterial infections and their harmful sequelae. Development of mixtures of inhibitors or a polyvalent inhibitor is under investigation, since many infectious agents express multiple specificities. Multiple molecular mechanisms of adhesion are required to initiate infection, and effective anti-adhesion strategies will need to address both bacterial and host site particularities.

Authors
Abraham, SN; Sharon, N; Ofek, I; Schwartzman, JD
MLA Citation
Abraham, SN, Sharon, N, Ofek, I, and Schwartzman, JD. "Adhesion and Colonization." Molecular Medical Microbiology: Second Edition. November 26, 2014. 409-421.
Source
scopus
Volume
1-3
Publish Date
2014
Start Page
409
End Page
421
DOI
10.1016/B978-0-12-397169-2.00024-X

S1P-Dependent trafficking of intracellular yersinia pestis through lymph nodes establishes Buboes and systemic infection.

Pathologically swollen lymph nodes (LNs), or buboes, characterize Yersinia pestis infection, yet how they form and function is unknown. We report that colonization of the draining LN (dLN) occurred due to trafficking of infected dendritic cells and monocytes in temporally distinct waves in response to redundant chemotactic signals, including through CCR7, CCR2, and sphingosine-1-phospate (S1P) receptors. Retention of multiple subsets of phagocytes within peripheral LNs using the S1P receptor agonist FTY720 or S1P1-specific agonist SEW2871 increased survival, reduced colonization of downstream LNs, and limited progression to transmission-associated septicemic or pneumonic disease states. Conditional deletion of S1P1 in mononuclear phagocytes abolished node-to-node trafficking of infected cells. Thus, Y. pestis-orchestrated LN remodeling promoted its dissemination via host cells through the lymphatic system but can be blocked by prevention of leukocyte egress from DLNs. These findings define a novel trafficking route of mononuclear phagocytes and identify S1P as a therapeutic target during infection.

Authors
St John, AL; Ang, WXG; Huang, M-N; Kunder, CA; Chan, EW; Gunn, MD; Abraham, SN
MLA Citation
St John, AL, Ang, WXG, Huang, M-N, Kunder, CA, Chan, EW, Gunn, MD, and Abraham, SN. "S1P-Dependent trafficking of intracellular yersinia pestis through lymph nodes establishes Buboes and systemic infection." Immunity 41.3 (September 2014): 440-450.
PMID
25238098
Source
epmc
Published In
Immunity
Volume
41
Issue
3
Publish Date
2014
Start Page
440
End Page
450
DOI
10.1016/j.immuni.2014.07.013

Cromolyn ameliorates acute and chronic injury in a rat lung transplant model.

Mast cells have been associated with obliterative bronchiolitis (OB) in human pulmonary allografts, although their role in the development of OB remains unknown.In this study, we evaluated the role of mast cells in pulmonary allograft rejection using an orthotopic rat pulmonary allograft model that utilizes chronic aspiration of gastric fluid to reliably obtain OB. Pulmonary allograft recipients (n = 35) received chronic aspiration of gastric fluid with (n = 10) and without (n = 16) treatment with a mast cell membrane stabilizer, cromolyn sodium, or chronic aspiration with normal saline (n = 9) as a control.The acute graft injury associated with long ischemic time in the model (6 hours total ischemic time; typical acute graft injury rate ~30%) was apparently blocked by cromolyn, because peri-operative mortality associated with the acute graft injury was not observed in any of the animals receiving cromolyn (p = 0.045). Further, the rats receiving cromolyn developed significantly fewer OB lesions than those treated with gastric fluid alone (p < 0.001), with a mean reduction of 46% of the airways affected.These findings provide impetus for further studies aimed at elucidating the effects of cromolyn and the role of mast cells in pulmonary allotransplantation.

Authors
Chang, J-C; Leung, J; Tang, T; Holzknecht, ZE; Hartwig, MG; Duane Davis, R; Parker, W; Abraham, SN; Lin, SS
MLA Citation
Chang, J-C, Leung, J, Tang, T, Holzknecht, ZE, Hartwig, MG, Duane Davis, R, Parker, W, Abraham, SN, and Lin, SS. "Cromolyn ameliorates acute and chronic injury in a rat lung transplant model." The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 33.7 (July 2014): 749-757.
PMID
24768366
Source
epmc
Published In
The Journal of Heart and Lung Transplantation
Volume
33
Issue
7
Publish Date
2014
Start Page
749
End Page
757
DOI
10.1016/j.healun.2014.03.004

Kidney α-intercalated cells and lipocalin 2: defending the urinary tract.

A growing body of evidence indicates that the kidneys contribute substantially to immune defense against pathogens in the urinary tract. In this issue, Paragas et al. report that α-intercalated cells (A-ICs) within the nephron collecting duct sense infecting Gram-negative bacteria, resulting in simultaneously secretion of the iron chelating protein lipocalin 2 (LCN2) and protons, which acidify the urine. A-IC-specific LCN2 and proton secretion markedly reduced the ability of infecting uropathogenic E. coli (UPEC) to grow and sustain infection. The capacity of A-ICs to sense and actively promote clearance of infecting bacteria in the lower urinary tract represents a novel function for these specialized kidney cells, which are best known for their role in modulating acid-base homeostasis.

Authors
Miao, Y; Abraham, SN
MLA Citation
Miao, Y, and Abraham, SN. "Kidney α-intercalated cells and lipocalin 2: defending the urinary tract." The Journal of clinical investigation 124.7 (July 2014): 2844-2846.
PMID
24937424
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
7
Publish Date
2014
Start Page
2844
End Page
2846
DOI
10.1172/jci76630

Peeing pentraxins.

Antimicrobial agents secreted into urine potentially play a powerful role in the defense of the urinary tract. In this issue of Immunity, Jaillon et al. (2014) describe a role for pentraxin 3 molecules in complementing the host's cellular innate immune responses to uropathogens.

Authors
Miao, Y; Abraham, SN
MLA Citation
Miao, Y, and Abraham, SN. "Peeing pentraxins." Immunity 40.4 (April 2014): 460-462.
PMID
24745330
Source
epmc
Published In
Immunity
Volume
40
Issue
4
Publish Date
2014
Start Page
460
End Page
462
DOI
10.1016/j.immuni.2014.03.006

Salmonella Typhimurium Impedes Innate Immunity With a Mast Cell-Suppressing Tyrosine Phosphatase Sptp

Authors
Choi, HW; Brooking, R; Neupane, S; Lee, C-J; Miao, E; Staats, HF; Abraham, SN
MLA Citation
Choi, HW, Brooking, R, Neupane, S, Lee, C-J, Miao, E, Staats, HF, and Abraham, SN. "Salmonella Typhimurium Impedes Innate Immunity With a Mast Cell-Suppressing Tyrosine Phosphatase Sptp." February 2014.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
133
Issue
2
Publish Date
2014
Start Page
AB247
End Page
AB247

Cromolyn ameliorates acute and chronic injury in a rat lung transplant model

Background Mast cells have been associated with obliterative bronchiolitis (OB) in human pulmonary allografts, although their role in the development of OB remains unknown. Methods In this study, we evaluated the role of mast cells in pulmonary allograft rejection using an orthotopic rat pulmonary allograft model that utilizes chronic aspiration of gastric fluid to reliably obtain OB. Pulmonary allograft recipients (n = 35) received chronic aspiration of gastric fluid with (n = 10) and without (n = 16) treatment with a mast cell membrane stabilizer, cromolyn sodium, or chronic aspiration with normal saline (n = 9) as a control. Results The acute graft injury associated with long ischemic time in the model (6 hours total ischemic time; typical acute graft injury rate ~30%) was apparently blocked by cromolyn, because peri-operative mortality associated with the acute graft injury was not observed in any of the animals receiving cromolyn (p = 0.045). Further, the rats receiving cromolyn developed significantly fewer OB lesions than those treated with gastric fluid alone (p < 0.001), with a mean reduction of 46% of the airways affected. Conclusions These findings provide impetus for further studies aimed at elucidating the effects of cromolyn and the role of mast cells in pulmonary allotransplantation. © 2014 International Society for Heart and Lung Transplantation.

Authors
Chang, JC; Leung, J; Tang, T; Holzknecht, ZE; Hartwig, MG; Duane Davis, R; Parker, W; Abraham, SN; Lin, SS
MLA Citation
Chang, JC, Leung, J, Tang, T, Holzknecht, ZE, Hartwig, MG, Duane Davis, R, Parker, W, Abraham, SN, and Lin, SS. "Cromolyn ameliorates acute and chronic injury in a rat lung transplant model." Journal of Heart and Lung Transplantation 33.7 (January 1, 2014): 749-757.
Source
scopus
Published In
The Journal of Heart and Lung Transplantation
Volume
33
Issue
7
Publish Date
2014
Start Page
749
End Page
757
DOI
10.1016/j.healun.2014.03.004

Salmonella Typhimurium Impedes Innate Immunity with a Mast-Cell-Suppressing Protein Tyrosine Phosphatase, SptP

The virulence of Salmonella is linked to its invasive capacity and suppression of adaptive immunity. This does not explain, however, the rapid dissemination of the pathogen after it breaches the gut. In our study, S. Typhimurium suppressed degranulation of local mast cells (MCs), resulting in limited neutrophil recruitment and restricting outflow of vascular contents into infection sites, thus facilitating bacterial spread. MC suppression was mediated by secreted effector protein (SptP), which shares structural homology with Yersinia YopH. SptP functioned by dephosphorylating the vesicle fusion protein N-ethylmalemide-sensitive factor and by blocking phosphorylation of Syk. Without SptP, orally challenged S. Typhimurium failed to suppress MC degranulation and exhibited limited colonization of the mesenteric lymph nodes. Administration of SptP to sites of E.coli infection markedly enhanced its virulence. Thus, SptP-mediated inactivation of local MCs is a powerful mechanism utilized by S. Typhimurium to impede early innate immunity. © 2013 Elsevier Inc.

Authors
Choi, HW; Brooking-Dixon, R; Neupane, S; Lee, CJ; Miao, EA; Staats, HF; Abraham, SN
MLA Citation
Choi, HW, Brooking-Dixon, R, Neupane, S, Lee, CJ, Miao, EA, Staats, HF, and Abraham, SN. "Salmonella Typhimurium Impedes Innate Immunity with a Mast-Cell-Suppressing Protein Tyrosine Phosphatase, SptP." Immunity 39.6 (December 12, 2013): 1108-1120.
PMID
24332031
Source
scopus
Published In
Immunity
Volume
39
Issue
6
Publish Date
2013
Start Page
1108
End Page
1120
DOI
10.1016/j.immuni.2013.11.009

Bacterial adhesion

© 2013 Springer-Verlag Berlin Heidelberg. All rights are reserved. Although bacteria adhere to many different types of surfaces present in their habitat, this review focuses on bacterial adhesion to animal cells and tissues as a first step in the ability of pathogens to colonize and subsequently cause tissue damage. Accordingly, basic principles that govern the interaction of bacterial adhesins to their cognate receptors on animal cells are presented, such as fimbriae as adhesin structures. Significantly, we discuss the types of receptor-adhesin relationship, the phenomenon of multiple adhesins each specific for distinct receptors produced by pathogenic clones, the identity of glycoconjugates as receptors for lectins that serve as adhesins, and the interaction of bacterial adhesins with the extracellular matrix on animal tissues. Finally, a specific section is devoted to recent developments in preventing or treating infections by blocking bacterial adhesion to animal cells. In this context, a review of the different approaches of antiadhesion therapy is discussed, including the use of receptor and adhesin analogs, dietary constituents, sub-lethal concentrations of antibiotics, and adhesin-based vaccines. A discussion and summary of these topics focus on the in vivo data, including human trials, whereby plant extracts are used as a source of antiadhesion agents to prevent or treat urinary tract infections caused by Escherichia coli and infectious gastritis or peptic ulcer diseases induced by Helicobacter pylori and to maintain oral health.

Authors
Ofek, I; Bayer, EA; Abraham, SN
MLA Citation
Ofek, I, Bayer, EA, and Abraham, SN. "Bacterial adhesion." The Prokaryotes: Human Microbiology. November 1, 2013. 107-123.
Source
scopus
Publish Date
2013
Start Page
107
End Page
123
DOI
10.1007/978-3-642-30144-5_50

A mastoparan-derived peptide has broad-spectrum antiviral activity against enveloped viruses.

Broad-spectrum antiviral drugs are urgently needed to treat individuals infected with new and re-emerging viruses, or with viruses that have developed resistance to antiviral therapies. Mammalian natural host defense peptides (mNHP) are short, usually cationic, peptides that have direct antimicrobial activity, and which in some instances activate cell-mediated antiviral immune responses. Although mNHP have potent activity in vitro, efficacy trials in vivo of exogenously provided mNHP have been largely disappointing, and no mNHP are currently licensed for human use. Mastoparan is an invertebrate host defense peptide that penetrates lipid bilayers, and we reasoned that a mastoparan analog might interact with the lipid component of virus membranes and thereby reduce infectivity of enveloped viruses. Our objective was to determine whether mastoparan-derived peptide MP7-NH2 could inactivate viruses of multiple types, and whether it could stimulate cell-mediated antiviral activity. We found that MP7-NH2 potently inactivated a range of enveloped viruses. Consistent with our proposed mechanism of action, MP7-NH2 was not efficacious against a non-enveloped virus. Pre-treatment of cells with MP7-NH2 did not reduce the amount of virus recovered after infection, which suggested that the primary mechanism of action in vitro was direct inactivation of virus by MP7-NH2. These results demonstrate for the first time that a mastoparan derivative has broad-spectrum antiviral activity in vitro and suggest that further investigation of the antiviral properties of mastoparan peptides in vivo is warranted.

Authors
Sample, CJ; Hudak, KE; Barefoot, BE; Koci, MD; Wanyonyi, MS; Abraham, S; Staats, HF; Ramsburg, EA
MLA Citation
Sample, CJ, Hudak, KE, Barefoot, BE, Koci, MD, Wanyonyi, MS, Abraham, S, Staats, HF, and Ramsburg, EA. "A mastoparan-derived peptide has broad-spectrum antiviral activity against enveloped viruses." Peptides 48 (October 2013): 96-105.
PMID
23891650
Source
pubmed
Published In
Peptides
Volume
48
Publish Date
2013
Start Page
96
End Page
105
DOI
10.1016/j.peptides.2013.07.014

Intestinal mast cells mediate gut injury and systemic inflammation in a rat model of deep hypothermic circulatory arrest.

OBJECTIVE: Cardiac surgery, especially when employing cardiopulmonary bypass and deep hypothermic circulatory arrest, is associated with systemic inflammatory responses that significantly affect morbidity and mortality. Intestinal perfusion abnormalities have been implicated in such responses, but the mechanisms linking local injury and systemic inflammation remain unclear. Intestinal mast cells are specialized immune cells that secrete various preformed effectors in response to cellular stress. We hypothesized that mast cells are activated in a microenvironment shaped by intestinal ischemia/reperfusion, and investigated local and systemic consequences. DESIGN: Rat model of deep hypothermic circulatory arrest. SETTING: University research laboratory. SUBJECTS: Twelve- to 14-week-old male Sprague-Dawley rats. INTERVENTIONS: Rats were anesthetized and cooled to 16°C to 18°C on cardiopulmonary bypass before instituting deep hypothermic circulatory arrest for 45 minutes. Specimens were harvested following rewarming and 2 hours of recovery. MEASUREMENTS AND MAIN RESULTS: Significant intestinal barrier disruption was found, together with macro- and microscopic evidence of ischemia/reperfusion injury in ileum and colon, but not in the lungs or kidneys. Immunofluorescence and toluidine blue staining revealed increased numbers of mast cells and their activation in the gut. In animals pretreated with the mast cell stabilizer, cromolyn sodium, mast cell degranulation was blocked, and intestinal morphology and barrier function were preserved following deep hypothermic circulatory arrest. Furthermore, cromolyn sodium treatment was associated with reduced intestinal neutrophil influx and blunted systemic release of proinflammatory cytokines. CONCLUSION: Our data provide primary evidence that intestinal ischemia/reperfusion is a leading pathophysiologic process in a rat model of deep hypothermic circulatory arrest, and that intestinal injury, and local and systemic inflammatory responses are critically dependent on mast cell activation. This identifies intestinal mast cells as central players in deep hypothermic circulatory arrest-associated responses, and opens novel therapeutic possibilities for patients undergoing this procedure.

Authors
Karhausen, J; Qing, M; Gibson, A; Moeser, AJ; Griefingholt, H; Hale, LP; Abraham, SN; Mackensen, GB
MLA Citation
Karhausen, J, Qing, M, Gibson, A, Moeser, AJ, Griefingholt, H, Hale, LP, Abraham, SN, and Mackensen, GB. "Intestinal mast cells mediate gut injury and systemic inflammation in a rat model of deep hypothermic circulatory arrest." Crit Care Med 41.9 (September 2013): e200-e210.
PMID
23478660
Source
pubmed
Published In
Critical Care Medicine
Volume
41
Issue
9
Publish Date
2013
Start Page
e200
End Page
e210
DOI
10.1097/CCM.0b013e31827cac7a

Interplay between vesicoureteric reflux and kidney infection in the development of reflux nephropathy in mice.

Vesicoureteric reflux (VUR) is a common congenital defect of the urinary tract that is usually discovered after a child develops a urinary tract infection. It is associated with reflux nephropathy, a renal lesion characterized by the presence of chronic tubulointersitial inflammation and fibrosis. Most patients are diagnosed with reflux nephropathy after one or more febrile urinary tract infections, suggesting a potential role for infection in its development. We have recently shown that the C3H mouse has a 100% incidence of VUR. Here, we evaluate the roles of VUR and uropathogenic Escherichia coli infection in the development of reflux nephropathy in the C3H mouse. We find that VUR in combination with sustained kidney infection is crucial to the development of reflux nephropathy, whereas sterile reflux alone fails to induce reflux nephropathy. A single bout of kidney infection without reflux fails to induce reflux nephropathy. The host immune response to infection was examined in two refluxing C3H substrains, HeN and HeJ. HeJ mice, which have a defect in innate immunity and bacterial clearance, demonstrate more significant renal inflammation and reflux nephropathy compared with HeN mice. These studies demonstrate the crucial synergy between VUR, sustained kidney infection and the host immune response in the development of reflux nephropathy in a mouse model of VUR.

Authors
Bowen, SE; Watt, CL; Murawski, IJ; Gupta, IR; Abraham, SN
MLA Citation
Bowen, SE, Watt, CL, Murawski, IJ, Gupta, IR, and Abraham, SN. "Interplay between vesicoureteric reflux and kidney infection in the development of reflux nephropathy in mice." Disease models & mechanisms 6.4 (July 2013): 934-941.
PMID
23519031
Source
epmc
Published In
Disease models & mechanisms
Volume
6
Issue
4
Publish Date
2013
Start Page
934
End Page
941
DOI
10.1242/dmm.011650

Innate immunity and its regulation by mast cells.

Mast cells (MCs), which are granulated tissue-resident cells of hematopoietic lineage, constitute a major sensory arm of the innate immune system. In this review we discuss the evidence supporting the dual role of MCs, both as sentinels for invading pathogens and as regulatory cells throughout the course of acute inflammation, from its initiation to resolution. This versatility is dependent on the ability of MCs to detect pathogens and danger signals and release a unique panel of mediators to promote pathogen-specific clearance mechanisms, such as through cellular recruitment or vascular permeability. It is increasingly understood that MCs also contribute to the regulated contraction of immune activation that occurs within tissues as inflammation resolves. This overarching regulatory control over innate immune processes has made MCs successful targets to purposefully enhance or, alternatively, suppress MC responses in multiple therapeutic contexts.

Authors
St John, AL; Abraham, SN
MLA Citation
St John, AL, and Abraham, SN. "Innate immunity and its regulation by mast cells." J Immunol 190.9 (May 1, 2013): 4458-4463. (Review)
PMID
23606723
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
190
Issue
9
Publish Date
2013
Start Page
4458
End Page
4463
DOI
10.4049/jimmunol.1203420

Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage.

Dengue Virus (DENV), a flavivirus spread by mosquito vectors, can cause vascular leakage and hemorrhaging. However, the processes that underlie increased vascular permeability and pathological plasma leakage during viral hemorrhagic fevers are largely unknown. Mast cells (MCs) are activated in vivo during DENV infection, and we show that this elevates systemic levels of their vasoactive products, including chymase, and promotes vascular leakage. Treatment of infected animals with MC-stabilizing drugs or a leukotriene receptor antagonist restores vascular integrity during experimental DENV infection. Validation of these findings using human clinical samples revealed a direct correlation between MC activation and DENV disease severity. In humans, the MC-specific product, chymase, is a predictive biomarker distinguishing dengue fever (DF) and dengue hemorrhagic fever (DHF). Additionally, our findings reveal MCs as potential therapeutic targets to prevent DENV-induced vasculopathy, suggesting MC-stabilizing drugs should be evaluated for their effectiveness in improving disease outcomes during viral hemorrhagic fevers. DOI:http://dx.doi.org/10.7554/eLife.00481.001.

Authors
St John, AL; Rathore, APS; Raghavan, B; Ng, M-L; Abraham, SN
MLA Citation
St John, AL, Rathore, APS, Raghavan, B, Ng, M-L, and Abraham, SN. "Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage. (Published online)" Elife 2 (April 30, 2013): e00481-.
Website
http://hdl.handle.net/10161/12468
PMID
23638300
Source
pubmed
Published In
eLife
Volume
2
Publish Date
2013
Start Page
e00481
DOI
10.7554/eLife.00481

A comparison of non-toxin vaccine adjuvants for their ability to enhance the immunogenicity of nasally-administered anthrax recombinant protective antigen.

Development of nasal immunization for human use is hindered by the lack of acceptable adjuvants. Although CT is an effective adjuvant, its toxicity will likely prevent its use in nasal vaccines. This study compared non-toxin adjuvants to CT for their ability to induce protective antibody responses with nasal immunization. C3H/HeN and C57BL/6 mice were immunized with rPA formulated with the following adjuvants: CT, IL-1α, LPS, CpG, Pam3CSK4, 3M-019, resiquimod/R848 or c48/80. Serum and nasal wash cytokine concentrations were monitored 6h post-vaccination as biomarkers for acute activation of the innate immune system. Not all of the adjuvants induced significant changes in innate serum or nasal wash cytokines, but when changes were observed, the cytokine signatures were unique for each adjuvant. All adjuvants except Pam3CSK4 induced significantly increased anti-rPA serum IgG titers in both strains of mice, while only IL-1α, c48/80 and CpG enhanced mucosal anti-rPA IgA. Pam3CSK4 was the only adjuvant unable to enhance the induction of serum LeTx-neutralizing antibodies in C3H/HeN mice while c48/80 was the only adjuvant to induce increased serum LeTx-neutralizing antibodies in C57BL/6 mice. Only CT enhanced total serum IgE in C3H/HeN mice while IL-1α enhanced total serum IgE in C57BL/6 mice. The adjuvant influenced antigen-specific serum IgG subclass and T cell cytokine profiles, but these responses did not correlate with the induction of LeTx-neutralizing activity. Our results demonstrate the induction of diverse innate and adaptive immune responses by non-toxin nasal vaccine adjuvants that lead to protective humoral immunity comparable to CT and that these responses may be influenced by the host strain.

Authors
Gwinn, WM; Johnson, BT; Kirwan, SM; Sobel, AE; Abraham, SN; Gunn, MD; Staats, HF
MLA Citation
Gwinn, WM, Johnson, BT, Kirwan, SM, Sobel, AE, Abraham, SN, Gunn, MD, and Staats, HF. "A comparison of non-toxin vaccine adjuvants for their ability to enhance the immunogenicity of nasally-administered anthrax recombinant protective antigen." Vaccine 31.11 (March 1, 2013): 1480-1489.
PMID
23352329
Source
pubmed
Published In
Vaccine
Volume
31
Issue
11
Publish Date
2013
Start Page
1480
End Page
1489
DOI
10.1016/j.vaccine.2013.01.012

Mast cell interleukin-10 drives localized tolerance in chronic bladder infection.

The lower urinary tract's virtually inevitable exposure to external microbial pathogens warrants efficient tissue-specialized defenses to maintain sterility. The observation that the bladder can become chronically infected in combination with clinical observations that antibody responses after bladder infections are not detectable suggest defects in the formation of adaptive immunity and immunological memory. We have identified a broadly immunosuppressive transcriptional program specific to the bladder, but not the kidney, during infection of the urinary tract that is dependent on tissue-resident mast cells (MCs). This involves localized production of interleukin-10 and results in suppressed humoral and cell-mediated responses and bacterial persistence. Therefore, in addition to the previously described role of MCs orchestrating the early innate immunity during bladder infection, they subsequently play a tissue-specific immunosuppressive role. These findings may explain the prevalent recurrence of bladder infections and suggest the bladder as a site exhibiting an intrinsic degree of MC-maintained immune privilege.

Authors
Chan, CY; St John, AL; Abraham, SN
MLA Citation
Chan, CY, St John, AL, and Abraham, SN. "Mast cell interleukin-10 drives localized tolerance in chronic bladder infection." Immunity 38.2 (February 21, 2013): 349-359.
PMID
23415912
Source
pubmed
Published In
Immunity
Volume
38
Issue
2
Publish Date
2013
Start Page
349
End Page
359
DOI
10.1016/j.immuni.2012.10.019

A mast cell degranulation screening assay for the identification of novel mast cell activating agents

The development and use of vaccines and their ability to prevent infection/disease is a shining example of the benefit of biomedical research. Modern vaccines often utilize subunit immunogens that exhibit minimal immunogenicity and require the use of adjuvants to maximize the induction of protective immune responses. We recently described a novel class of vaccine adjuvants, mast cell (MC) activators, that exhibit safe and effective vaccine adjuvant activity when administered by intranasal or intradermal routes. A compound library containing 580 functionalized benzopyrans, a structural motif found in a diverse array of natural and designed bioactive compounds, was screened using a MC degranulation assay to identify novel MC activating compounds for future evaluation as novel vaccine adjuvants. This approach identified 12 novel MC degranulating compounds. Therefore, MC degranulation can be used to reliably detect novel compounds for evaluation as adjuvants for use in mucosal vaccine strategies. This journal is © The Royal Society of Chemistry 2013.

Authors
Staats, HF; Kirwan, SM; Choi, HW; Shelburne, CP; Abraham, SN; Leung, GYC; Chen, DY-K
MLA Citation
Staats, HF, Kirwan, SM, Choi, HW, Shelburne, CP, Abraham, SN, Leung, GYC, and Chen, DY-K. "A mast cell degranulation screening assay for the identification of novel mast cell activating agents." MedChemComm 4.1 (2013): 88-94.
PMID
23667736
Source
scival
Published In
MedChemComm
Volume
4
Issue
1
Publish Date
2013
Start Page
88
End Page
94
DOI
10.1039/c2md20073b

Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage

Dengue Virus (DENV), a flavivirus spread by mosquito vectors, can cause vascular leakage and hemorrhaging. However, the processes that underlie increased vascular permeability and pathological plasma leakage during viral hemorrhagic fevers are largely unknown. Mast cells (MCs) are activated in vivo during DENV infection, and we show that this elevates systemic levels of their vasoactive products, including chymase, and promotes vascular leakage. Treatment of infected animals with MC-stabilizing drugs or a leukotriene receptor antagonist restores vascular integrity during experimental DENV infection. Validation of these findings using human clinical samples revealed a direct correlation between MC activation and DENV disease severity. In humans, the MC-specific product, chymase, is a predictive biomarker distinguishing dengue fever (DF) and dengue hemorrhagic fever (DHF). Additionally, our findings reveal MCs as potential therapeutic targets to prevent DENV-induced vasculopathy, suggesting MC-stabilizing drugs should be evaluated for their effectiveness in improving disease outcomes during viral hemorrhagic fevers. Copyright St John et al.

Authors
John, ALS; Rathore, APS; Raghavan, B; Ng, M-L; Abraham, SN
MLA Citation
John, ALS, Rathore, APS, Raghavan, B, Ng, M-L, and Abraham, SN. "Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage." eLife 2013.2 (2013).
Source
scival
Published In
eLife
Volume
2013
Issue
2
Publish Date
2013
DOI
10.7554/eLife.00481.001

Intestinal mast cells mediate gut injury and systemic inflammation in a rat model of deep hypothermic circulatory arrest

Objective:: Cardiac surgery, especially when employing cardiopulmonary bypass and deep hypothermic circulatory arrest, is associated with systemic inflammatory responses that significantly affect morbidity and mortality. Intestinal perfusion abnormalities have been implicated in such responses, but the mechanisms linking local injury and systemic inflammation remain unclear. Intestinal mast cells are specialized immune cells that secrete various preformed effectors in response to cellular stress. We hypothesized that mast cells are activated in a microenvironment shaped by intestinal ischemia/reperfusion, and investigated local and systemic consequences. Design:: Rat model of deep hypothermic circulatory arrest. Setting:: University research laboratory. Subjects:: Twelve-to 14-week-old male Sprague-Dawley rats. Interventions:: Rats were anesthetized and cooled to 16 C to 18 C on cardiopulmonary bypass before instituting deep hypothermic circulatory arrest for 45 minutes. Specimens were harvested following rewarming and 2 hours of recovery. Measurements and Main Results:: Significant intestinal barrier disruption was found, together with macro-and microscopic evidence of ischemia/reperfusion injury in ileum and colon, but not in the lungs or kidneys. Immunofluorescence and toluidine blue staining revealed increased numbers of mast cells and their activation in the gut. In animals pretreated with the mast cell stabilizer, cromolyn sodium, mast cell degranulation was blocked, and intestinal morphology and barrier function were preserved following deep hypothermic circulatory arrest. Furthermore, cromolyn sodium treatment was associated with reduced intestinal neutrophil influx and blunted systemic release of proinflammatory cytokines. Conclusion:: Our data provide primary evidence that intestinal ischemia/reperfusion is a leading pathophysiologic process in a rat model of deep hypothermic circulatory arrest, and that intestinal injury, and local and systemic inflammatory responses are critically dependent on mast cell activation. This identifies intestinal mast cells as central players in deep hypothermic circulatory arrest-associated responses, and opens novel therapeutic possibilities for patients undergoing this procedure. Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Authors
Karhausen, J; Qing, M; Gibson, A; Moeser, AJ; Griefingholt, H; Hale, LP; Abraham, SN; MacKensen, GB
MLA Citation
Karhausen, J, Qing, M, Gibson, A, Moeser, AJ, Griefingholt, H, Hale, LP, Abraham, SN, and MacKensen, GB. "Intestinal mast cells mediate gut injury and systemic inflammation in a rat model of deep hypothermic circulatory arrest." Critical Care Medicine 41.9 (2013): e200-e210.
Source
scival
Published In
Critical Care Medicine
Volume
41
Issue
9
Publish Date
2013
Start Page
e200
End Page
e210
DOI
10.1097/CCM.0b013e31827cac7a

Mast cell TNF receptors regulate responses to Mycoplasma pneumoniae in surfactant protein A (SP-A)-/- mice.

BACKGROUND: Mycoplasma pneumoniae (Mp) frequently colonizes the airways of patients with chronic asthma and likely contributes to asthma exacerbations. We previously reported that mice lacking surfactant protein A (SP-A) have increased airway hyperresponsiveness (AHR) during M pneumoniae infection versus wild-type mice mediated by TNF-α. Mast cells (MCs) have been implicated in AHR in asthma models and produce and respond to TNF-α. OBJECTIVE: Determine the contribution of MC/TNF interactions to AHR in airways lacking functional SP-A during Mp infection. METHODS: Bronchoalveolar lavage fluid was collected from healthy and asthmatic subjects to examine TNF-α levels and M pneumoniae positivity. To determine how SP-A interactions with MCs regulate airway homeostasis, we generated mice lacking both SP-A and MCs (SP-A(-/-)Kit(W-sh/W-sh)) and infected them with M pneumoniae. RESULTS: Our findings indicate that high TNF-α levels correlate with M pneumoniae positivity in human asthmatic patients and that human SP-A inhibits M pneumoniae-stimulated transcription and release of TNF-α by MCs, implicating a protective role for SP-A. MC numbers increase in M pneumoniae-infected lungs, and airway reactivity is dramatically attenuated when MCs are absent. Using SP-A(-/-)Kit(W-sh/W-sh) mice engrafted with TNF-α(-/-) or TNF receptor (TNF-R)(-/-) MCs, we found that TNF-α activation of MCs through the TNF-R, but not MC-derived TNF-α, leads to augmented AHR during M pneumoniae infection when SP-A is absent. Additionally, M pneumoniae-infected SP-A(-/-)Kit(W-sh/W-sh) mice engrafted with TNF-α(-/-) or TNF-R(-/-) MCs have decreased mucus production compared with that seen in mice engrafted with wild-type MCs, whereas burden was unaffected. CONCLUSION: Our data highlight a previously unappreciated but vital role for MCs as secondary responders to TNF-α during the host response to pathogen infection.

Authors
Hsia, BJ; Ledford, JG; Potts-Kant, EN; Nikam, VS; Lugogo, NL; Foster, WM; Kraft, M; Abraham, SN; Wright, JR
MLA Citation
Hsia, BJ, Ledford, JG, Potts-Kant, EN, Nikam, VS, Lugogo, NL, Foster, WM, Kraft, M, Abraham, SN, and Wright, JR. "Mast cell TNF receptors regulate responses to Mycoplasma pneumoniae in surfactant protein A (SP-A)-/- mice." J Allergy Clin Immunol 130.1 (July 2012): 205-14.e2.
PMID
22502799
Source
pubmed
Published In
Journal of Allergy and Clinical Immunology
Volume
130
Issue
1
Publish Date
2012
Start Page
205
End Page
14.e2
DOI
10.1016/j.jaci.2012.03.002

Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata.

Candida glabrata is an emerging human fungal pathogen that is frequently drug tolerant, resulting in difficulties in treatment and a higher mortality in immunocompromised patients. The calcium-activated protein phosphatase calcineurin plays critical roles in controlling drug tolerance, hyphal growth, and virulence in diverse fungal pathogens via distinct mechanisms involving survival in serum or growth at host temperature (37° and higher). Here, we comprehensively studied the calcineurin signaling cascade in C. glabrata and found novel and uncharacterized functions of calcineurin and its downstream target Crz1 in governing thermotolerance, intracellular architecture, and pathogenesis in murine ocular, urinary tract, and systemic infections. This represents a second independent origin of a role for calcineurin in thermotolerant growth of a major human fungal pathogen, distinct from that which arose independently in Cryptococcus neoformans. Calcineurin also promotes survival of C. glabrata in serum via mechanisms distinct from C. albicans and thereby enables establishment of tissue colonization in a murine systemic infection model. To understand calcineurin signaling in detail, we performed global transcript profiling analysis and identified calcineurin- and Crz1-dependent genes in C. glabrata involved in cell wall biosynthesis, heat shock responses, and calcineurin function. Regulators of calcineurin (RCN) are a novel family of calcineurin modifiers, and two members of this family were identified in C. glabrata: Rcn1 and Rcn2. Our studies demonstrate that Rcn2 expression is controlled by calcineurin and Crz1 to function as a feedback inhibitor of calcineurin in a circuit required for calcium tolerance in C. glabrata. In contrast, the calcineurin regulator Rcn1 activates calcineurin signaling. Interestingly, neither Rcn1 nor Rcn2 is required for virulence in a murine systemic infection model. Taken together, our findings show that calcineurin signaling plays critical roles in thermotolerance and virulence, and that Rcn1 and Rcn2 have opposing functions in controlling calcineurin signaling in C. glabrata.

Authors
Chen, Y-L; Konieczka, JH; Springer, DJ; Bowen, SE; Zhang, J; Silao, FGS; Bungay, AAC; Bigol, UG; Nicolas, MG; Abraham, SN; Thompson, DA; Regev, A; Heitman, J
MLA Citation
Chen, Y-L, Konieczka, JH, Springer, DJ, Bowen, SE, Zhang, J, Silao, FGS, Bungay, AAC, Bigol, UG, Nicolas, MG, Abraham, SN, Thompson, DA, Regev, A, and Heitman, J. "Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata." G3 (Bethesda, Md.) 2.6 (June 2012): 675-691.
PMID
22690377
Source
epmc
Published In
G3 (Bethesda, Md.)
Volume
2
Issue
6
Publish Date
2012
Start Page
675
End Page
691
DOI
10.1534/g3.112.002279

Plasticity in mast cell responses during bacterial infections.

Mast cells (MCs) have been implicated in orchestrating the host's early innate immune and adaptive immune responses in several models of acute bacterial infections. Most of this activity results in early clearance of the bacteria and timely resolution of infection. However, during chronic infections because of the prolonged nature of MC-bacterial interactions, the role of the MC in determining the fate of infection is markedly more complex. Depending on the nature of the pathogen, severity of infection, and its association with a preexisting inflammatory disease, MCs may promote rather than contain chronic infections and exacerbate their pathological sequellae.

Authors
Chan, CY; St John, AL; Abraham, SN
MLA Citation
Chan, CY, St John, AL, and Abraham, SN. "Plasticity in mast cell responses during bacterial infections." Curr Opin Microbiol 15.1 (February 2012): 78-84. (Review)
PMID
22055570
Source
pubmed
Published In
Current Opinion in Microbiology
Volume
15
Issue
1
Publish Date
2012
Start Page
78
End Page
84
DOI
10.1016/j.mib.2011.10.007

Nasal Immunization with Peanut Antigen and The Cationic Peptide Adjuvant Mastoparan 7 Induces Serum Humoral Immunity That Protects Peanut Allergic Mice Against Systemic Anaphylaxis

Authors
Johnson, BT; Kulis, M; Abraham, SN; Burks, AW; Staats, HF
MLA Citation
Johnson, BT, Kulis, M, Abraham, SN, Burks, AW, and Staats, HF. "Nasal Immunization with Peanut Antigen and The Cationic Peptide Adjuvant Mastoparan 7 Induces Serum Humoral Immunity That Protects Peanut Allergic Mice Against Systemic Anaphylaxis." February 2012.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
129
Issue
2
Publish Date
2012
Start Page
AB176
End Page
AB176

Increased Nitric Oxide Production Prevents Airway Hyperresponsiveness in Caveolin-1 Deficient Mice Following Endotoxin Exposure.

BACKGROUND: Caveolin-1, the hallmark protein of caveolae, is highly expressed within the lung in the epithelium, endothelium, and in immune cells. In addition to its classical roles in cholesterol metabolism and endocytosis, caveolin-1 has also been shown to be important in inflammatory signaling pathways. In particular, caveolin-1 is known to associate with the nitric oxide synthase enzymes, downregulating their activity. Endotoxins, which are are composed mainly of lipopolysaccharide (LPS), are found ubiquitously in the environment and can lead to the development of airway inflammation and increased airway hyperresponsiveness (AHR). METHODS: We compared the acute responses of wild-type and caveolin-1 deficient mice after LPS aerosol, a well-accepted mode of endotoxin exposure, to investigate the role of caveolin-1 in the development of environmental lung injury. RESULTS: Although the caveolin-1 deficient mice had greater lung inflammatory indices compared to wild-type mice, they exhibited reduced AHR following LPS exposure. The uncoupling of inflammation and AHR led us to investigate the role of caveolin-1 in the production of nitric oxide, which is known to act as a bronchodilator. The absence of caveolin-1 resulted in increased nitrite levels in the lavage fluid in both sham and LPS treated mice. Additionally, inducible nitric oxide synthase expression was increased in the lung tissue of caveolin-1 deficient mice following LPS exposure and administration of the potent and specific inhibitor 1400W increased AHR to levels comparable to wild-type mice. CONCLUSIONS: We attribute the relative airway hyporesponsiveness in the caveolin-1 deficient mice after LPS exposure to the specific role of caveolin-1 in mediating nitric oxide production.

Authors
Hsia, BJ; Pastva, AM; Giamberardino, CD; Potts-Kant, EN; Foster, WM; Que, LG; Abraham, SN; Wright, JR; Zaas, DW
MLA Citation
Hsia, BJ, Pastva, AM, Giamberardino, CD, Potts-Kant, EN, Foster, WM, Que, LG, Abraham, SN, Wright, JR, and Zaas, DW. "Increased Nitric Oxide Production Prevents Airway Hyperresponsiveness in Caveolin-1 Deficient Mice Following Endotoxin Exposure." J Allergy Ther Suppl 1.4 (January 25, 2012).
PMID
24273688
Source
pubmed
Published In
Journal of Allergy & Therapy
Volume
Suppl 1
Issue
4
Publish Date
2012
DOI
10.4172/2155-6121.S1-004

Synthetic mast-cell granules as adjuvants to promote and polarize immunity in lymph nodes.

Granules of mast cells (MCs) enhance adaptive immunity when, on activation, they are released as stable particles. Here we show that submicrometre particles modelled after MC granules augment immunity when used as adjuvants in vaccines. The synthetic particles, which consist of a carbohydrate backbone with encapsulated inflammatory mediators such as tumour necrosis factor, replicate attributes of MCs in vivo including the targeting of draining lymph nodes and the timed release of the encapsulated mediators. When used as an adjuvant during vaccination of mice with haemagglutinin from the influenza virus, the particles enhanced adaptive immune responses and increased survival of mice on lethal challenge. Furthermore, differential loading of the particles with the cytokine IL-12 directed the character of the response towards Th1 lymphocytes. The synthetic MC adjuvants replicate and enhance the functions of MCs during vaccination, and can be extended to polarize the resulting immunity.

Authors
St John, AL; Chan, CY; Staats, HF; Leong, KW; Abraham, SN
MLA Citation
St John, AL, Chan, CY, Staats, HF, Leong, KW, and Abraham, SN. "Synthetic mast-cell granules as adjuvants to promote and polarize immunity in lymph nodes. (Published online)" Nat Mater 11.3 (January 22, 2012): 250-257.
PMID
22266469
Source
pubmed
Published In
Nature Materials
Volume
11
Issue
3
Publish Date
2012
Start Page
250
End Page
257
DOI
10.1038/nmat3222

Stable dry powder formulation for nasal delivery of anthrax vaccine

There is a current biodefense interest in protection against anthrax. Here, we developed a new generation of stable and effective anthrax vaccine. We studied the immune response elicited by recombinant protective antigen (rPA) delivered intranasally with a novel mucosal adjuvant, a mast cell activator compound 48/80 (C48/80). The vaccine formulation was prepared in a powder form by spray-freeze-drying (SFD) under optimized conditions to produce particles with a target size of D 50 = 25μm, suitable for delivery to the rabbit nasal cavity. Physicochemical properties of the powder vaccines were characterized to assess their delivery and storage potential. Structural stability of rPA was confirmed by circular dichroism and attenuated total reflectance-Fourier transform infrared spectroscopy, whereas functional stability of rPA and C48/80 was monitored by cell-based assays. Animal study was performed using a unit-dose powder device for direct nasal application. Results showed that C48/80 provided effective mucosal adjuvant activity in rabbits. Freshly prepared SFD powder vaccine formulations or powders stored for over 2years at room temperature elicited significantly elevated serum PA-specific and lethal toxin neutralization antibody titers that were comparable to that induced by intramuscular immunization with rPA. Nasal delivery of this vaccine formulation may be a viable alternative to the currently licensed vaccine or an attractive vaccine platform for other mucosally transmitted diseases. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association.

Authors
Wang, SH; Kirwan, SM; Abraham, SN; Staats, HF; Hickey, AJ
MLA Citation
Wang, SH, Kirwan, SM, Abraham, SN, Staats, HF, and Hickey, AJ. "Stable dry powder formulation for nasal delivery of anthrax vaccine." Journal of Pharmaceutical Sciences 101.1 (2012): 31-47.
PMID
21905034
Source
scival
Published In
Journal of Pharmaceutical Sciences
Volume
101
Issue
1
Publish Date
2012
Start Page
31
End Page
47
DOI
10.1002/jps.22742

Mast cell modulation of the vascular and lymphatic endothelium.

Mast cells (MCs) promote a wide range of localized and systemic inflammatory responses. Their involvement in immediate as well as chronic inflammatory reactions at both local and distal sites points to an extraordinarily powerful immunoregulatory capacity with spatial and temporal versatility. MCs are preferentially found in close proximity to both vascular and lymphatic vessels. On activation, they undergo a biphasic secretory response involving the rapid release of prestored vasoactive mediators followed by de novo synthesized products. Many actions of MCs are related to their capacity to regulate vascular flow and permeability and to the recruitment of various inflammatory cells from the vasculature into inflammatory sites. These mediators often work in an additive fashion and achieve their inflammatory effects locally by directly acting on the vascular and lymphatic endothelia, but they also can affect distal sites. Along these lines, the lymphatic and endothelial vasculatures of the host act as a conduit for the dissemination of MC signals during inflammation. The central role of the MC-endothelial cell axis to immune homeostasis is emphasized by the fact that some of the most effective current treatments for inflammatory disorders are directed at interfering with this interaction.

Authors
Kunder, CA; St John, AL; Abraham, SN
MLA Citation
Kunder, CA, St John, AL, and Abraham, SN. "Mast cell modulation of the vascular and lymphatic endothelium." Blood 118.20 (November 17, 2011): 5383-5393. (Review)
PMID
21908429
Source
pubmed
Published In
Blood
Volume
118
Issue
20
Publish Date
2011
Start Page
5383
End Page
5393
DOI
10.1182/blood-2011-07-358432

Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance.

A wealth of evidence supports the essential contributions of mast cells (MCs) to immune defense against bacteria and parasites; however, the role of MCs in viral infections has not been defined. We now report that rodent, monkey, and human MCs are able to detect dengue virus (DENV), a lymphotropic, enveloped, single-stranded, positive-sense RNA virus that results in MC activation and degranulation. We observe that the response of MCs to DENV also involves the activation of antiviral intracellular host response pathways, melanoma differentiation-associated gene 5 (MDA5) and retinoic acid inducible gene 1 (RIG-I), and the de novo transcription of cytokines, including TNF-α and IFN-α, and chemokines, such as CCL5, CXCL12, and CX3CL1. This multifaceted response of MCs to DENV is consequential to the containment of DENV in vivo because, after s.c. infection, MC-deficient mice show increased viral burden within draining lymph nodes, which are known to be targeted organs during DENV spread, compared with MC-sufficient mice. This containment of DENV is linked to the MC-driven recruitment of natural killer and natural killer T cells into the infected skin. These findings support expanding the defined role of immunosurveillance by MCs to include viral pathogens.

Authors
St John, AL; Rathore, APS; Yap, H; Ng, M-L; Metcalfe, DD; Vasudevan, SG; Abraham, SN
MLA Citation
St John, AL, Rathore, APS, Yap, H, Ng, M-L, Metcalfe, DD, Vasudevan, SG, and Abraham, SN. "Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance." Proc Natl Acad Sci U S A 108.22 (May 31, 2011): 9190-9195.
PMID
21576486
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
22
Publish Date
2011
Start Page
9190
End Page
9195
DOI
10.1073/pnas.1105079108

Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation.

Allergic asthma is characterized by airway hyperresponsiveness, inflammation, and a cellular infiltrate dominated by eosinophils. Numerous epidemiological studies have related the exacerbation of allergic asthma with an increase in ambient inhalable particulate matter from air pollutants. This is because inhalable particles efficiently deliver airborne allergens deep into the airways, where they can aggravate allergic asthma symptoms. However, the cellular mechanisms by which inhalable particulate allergens (pAgs) potentiate asthmatic symptoms remain unknown, in part because most in vivo and in vitro studies exploring the pathogenesis of allergic asthma use soluble allergens (sAgs). Using a mouse model of allergic asthma, we found that, compared with their sAg counterparts, pAgs triggered markedly heightened airway hyperresponsiveness and pulmonary eosinophilia in allergen-sensitized mice. Mast cells (MCs) were implicated in this divergent response, as the differences in airway inflammatory responses provoked by the physical nature of the allergens were attenuated in MC-deficient mice. The pAgs were found to mediate MC-dependent responses by enhancing retention of pAg/IgE/FcεRI complexes within lipid raft–enriched, CD63(+) endocytic compartments, which prolonged IgE/FcεRI-initiated signaling and resulted in heightened cytokine responses. These results reveal how the physical attributes of allergens can co-opt MC endocytic circuitry and signaling responses to aggravate pathological responses of allergic asthma in mice.

Authors
Jin, C; Shelburne, CP; Li, G; Potts, EN; Riebe, KJ; Sempowski, GD; Foster, WM; Abraham, SN
MLA Citation
Jin, C, Shelburne, CP, Li, G, Potts, EN, Riebe, KJ, Sempowski, GD, Foster, WM, and Abraham, SN. "Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation." J Clin Invest 121.3 (March 2011): 941-955.
Website
http://hdl.handle.net/10161/2358
PMID
21285515
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
121
Issue
3
Publish Date
2011
Start Page
941
End Page
955
DOI
10.1172/JCI43584

Mucosal targeting of a BoNT/A subunit vaccine adjuvanted with a mast cell activator enhances induction of BoNT/A neutralizing antibodies in rabbits.

BACKGROUND: We previously reported that the immunogenicity of Hcβtre, a botulinum neurotoxin A (BoNT/A) immunogen, was enhanced by fusion to an epithelial cell binding domain, Ad2F, when nasally delivered to mice with cholera toxin (CT). This study was performed to determine if Ad2F would enhance the nasal immunogenicity of Hcβtre in rabbits, an animal model with a nasal cavity anatomy similar to humans. Since CT is not safe for human use, we also tested the adjuvant activity of compound 48/80 (C48/80), a mast cell activating compound previously determined to safely exhibit nasal adjuvant activity in mice. METHODS: New Zealand White or Dutch Belted rabbits were nasally immunized with Hcβtre or Hcβtre-Ad2F alone or combined with CT or C48/80, and serum samples were tested for the presence of Hcβtre-specific binding (ELISA) or BoNT/A neutralizing antibodies. RESULTS: Hcβtre-Ad2F nasally administered with CT induced serum anti-Hcβtre IgG ELISA and BoNT/A neutralizing antibody titers greater than those induced by Hcβtre + CT. C48/80 provided significant nasal adjuvant activity and induced BoNT/A-neutralizing antibodies similar to those induced by CT. CONCLUSIONS: Ad2F enhanced the nasal immunogenicity of Hcβtre, and the mast cell activator C48/80 was an effective adjuvant for nasal immunization in rabbits, an animal model with a nasal cavity anatomy similar to that in humans.

Authors
Staats, HF; Fielhauer, JR; Thompson, AL; Tripp, AA; Sobel, AE; Maddaloni, M; Abraham, SN; Pascual, DW
MLA Citation
Staats, HF, Fielhauer, JR, Thompson, AL, Tripp, AA, Sobel, AE, Maddaloni, M, Abraham, SN, and Pascual, DW. "Mucosal targeting of a BoNT/A subunit vaccine adjuvanted with a mast cell activator enhances induction of BoNT/A neutralizing antibodies in rabbits. (Published online)" PLoS One 6.1 (January 27, 2011): e16532-.
PMID
21304600
Source
pubmed
Published In
PloS one
Volume
6
Issue
1
Publish Date
2011
Start Page
e16532
DOI
10.1371/journal.pone.0016532

The mast cell in innate and adaptive immunity.

Mast cells (MCs) were once considered only as effector cells in pathogenic IgE- and IgG-mediated responses such as allergy. However, developments over the last 15 years have suggested that MCs have evolved in vertebrates as beneficial effector cells that are involved in the very first inflammatory responses generated during infection. This pro-inflammatory environment has been demonstrated to be important for initiating innate responses in many different models of infection and more recently, in the development of adaptive immunity as well. Interestingly this latter finding has led to the discovery that small MC-activating compounds can behave as adjuvants in vaccine formulations. Thus, our continued understanding of the MC in the context of infectious disease is likely to not only expand our scope of the MC in the normal processes of immunity, but provide new therapeutic targets to combat disease.

Authors
Shelburne, CP; Abraham, SN
MLA Citation
Shelburne, CP, and Abraham, SN. "The mast cell in innate and adaptive immunity." Adv Exp Med Biol 716 (2011): 162-185. (Review)
PMID
21713657
Source
pubmed
Published In
Advances in experimental medicine and biology
Volume
716
Publish Date
2011
Start Page
162
End Page
185
DOI
10.1007/978-1-4419-9533-9_10

Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10-deficient mice.

BACKGROUND: Inflammatory bowel disease (IBD) is hypothesized to result from stimulation of immune responses against resident intestinal bacteria within a genetically susceptible host. Mast cells may play a critical role in IBD pathogenesis, since they are typically located just beneath the intestinal mucosal barrier and can be activated by bacterial antigens. METHODOLOGY/PRINCIPAL FINDINGS: This study investigated effects of mast cells on inflammation and associated neoplasia in IBD-susceptible interleukin (IL)-10-deficient mice with and without mast cells. IL-10-deficient mast cells produced more pro-inflammatory cytokines in vitro both constitutively and when triggered, compared with wild type mast cells. However despite this enhanced in vitro response, mast cell-sufficient Il10(-/-) mice actually had decreased cecal expression of tumor necrosis factor (TNF) and interferon (IFN)-gamma mRNA, suggesting that mast cells regulate inflammation in vivo. Mast cell deficiency predisposed Il10(-/-) mice to the development of spontaneous colitis and resulted in increased intestinal permeability in vivo that preceded the development of colon inflammation. However, mast cell deficiency did not affect the severity of IBD triggered by non-steroidal anti-inflammatory agents (NSAID) exposure or helicobacter infection that also affect intestinal permeability. CONCLUSIONS/SIGNIFICANCE: Mast cells thus appear to have a primarily protective role within the colonic microenvironment by enhancing the efficacy of the mucosal barrier. In addition, although mast cells were previously implicated in progression of sporadic colon cancers, mast cells did not affect the incidence or severity of colonic neoplasia in this inflammation-associated model.

Authors
Chichlowski, M; Westwood, GS; Abraham, SN; Hale, LP
MLA Citation
Chichlowski, M, Westwood, GS, Abraham, SN, and Hale, LP. "Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10-deficient mice. (Published online)" PLoS One 5.8 (August 17, 2010): e12220-.
Website
http://hdl.handle.net/10161/4564
PMID
20808919
Source
pubmed
Published In
PloS one
Volume
5
Issue
8
Publish Date
2010
Start Page
e12220
DOI
10.1371/journal.pone.0012220

Mast cell-orchestrated immunity to pathogens.

Although mast cells were discovered more than a century ago, their functions beyond their role in allergic responses remained elusive until recently. However, there is a growing appreciation that an important physiological function of these cells is the recognition of pathogens and modulation of appropriate immune responses. Because of their ability to instantly release several pro-inflammatory mediators from intracellular stores and their location at the host-environment interface, mast cells have been shown to be crucial for optimal immune responses during infection. Mast cells seem to exert these effects by altering the inflammatory environment after detection of a pathogen and by mobilizing various immune cells to the site of infection and to draining lymph nodes. Interestingly, the character and timing of these responses can vary depending on the type of pathogen stimulus, location of pathogen recognition and sensitization state of the responding mast cells. Recent studies using mast cell activators as effective vaccine adjuvants show the potential of harnessing these cells to confer protective immunity against microbial pathogens.

Authors
Abraham, SN; St John, AL
MLA Citation
Abraham, SN, and St John, AL. "Mast cell-orchestrated immunity to pathogens." Nat Rev Immunol 10.6 (June 2010): 440-452. (Review)
PMID
20498670
Source
pubmed
Published In
Nature Reviews Immunology
Volume
10
Issue
6
Publish Date
2010
Start Page
440
End Page
452
DOI
10.1038/nri2782

New roles for mast cells in pathogen defense and allergic disease.

Mast cells (MC) are specialized exocytic cells that lie beneath the external surfaces of the body. For many decades, MCs were thought to primarily function as effector cells for IgE mediated allergic diseases. However, recent evidence indicates that MCs also function as important cells in immune surveillance. When activated by pathogens, MCs initiate innate and adaptive immune responses thereby resulting in protection against pathogens. The question remains if MC activation may also function in establishing immune responses against allergens and hence allergic disease. New studies suggest that MCs are not only the effector cell of allergy but may also be the initiator of allergy.

Authors
Hofmann, AM; Abraham, SN
MLA Citation
Hofmann, AM, and Abraham, SN. "New roles for mast cells in pathogen defense and allergic disease." Discovery medicine 9.45 (February 2010): 79-83. (Review)
PMID
20193631
Source
epmc
Published In
Discovery medicine
Volume
9
Issue
45
Publish Date
2010
Start Page
79
End Page
83

An In Vitro Model of Mast Cell Desensitization

Authors
Hofmann, AM; Jin, C; Staats, HF; Abraham, SN
MLA Citation
Hofmann, AM, Jin, C, Staats, HF, and Abraham, SN. "An In Vitro Model of Mast Cell Desensitization." February 2010.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
125
Issue
2
Publish Date
2010
Start Page
AB179
End Page
AB179

Cell biology and physiology of the uroepithelium.

The uroepithelium sits at the interface between the urinary space and underlying tissues, where it forms a high-resistance barrier to ion, solute, and water flux, as well as pathogens. However, the uroepithelium is not simply a passive barrier; it can modulate the composition of the urine, and it functions as an integral part of a sensory web in which it receives, amplifies, and transmits information about its external milieu to the underlying nervous and muscular systems. This review examines our understanding of uroepithelial regeneration and how specializations of the outermost umbrella cell layer, including tight junctions, surface uroplakins, and dynamic apical membrane exocytosis/endocytosis, contribute to barrier function and how they are co-opted by uropathogenic bacteria to infect the uroepithelium. Furthermore, we discuss the presence and possible functions of aquaporins, urea transporters, and multiple ion channels in the uroepithelium. Finally, we describe potential mechanisms by which the uroepithelium can transmit information about the urinary space to the other tissues in the bladder proper.

Authors
Khandelwal, P; Abraham, SN; Apodaca, G
MLA Citation
Khandelwal, P, Abraham, SN, and Apodaca, G. "Cell biology and physiology of the uroepithelium." Am J Physiol Renal Physiol 297.6 (December 2009): F1477-F1501. (Review)
PMID
19587142
Source
pubmed
Published In
American journal of physiology. Renal physiology
Volume
297
Issue
6
Publish Date
2009
Start Page
F1477
End Page
F1501
DOI
10.1152/ajprenal.00327.2009

New roles for mast cells in modulating allergic reactions and immunity against pathogens.

Mast cells (MCs) have primarily been associated with mediating the pathological secondary responses to allergens in sensitized hosts. In view of the recent evidence for a MC role in modulating primary immune responses to pathogens, the likelihood for a role of MCs in influencing primary immune response to allergens has grown. New evidence suggests that MCs drive the development of Th2 responses to allergens, particularly when allergen exposure occurs concomitantly with exposure to pathogen products present in the environment. These new roles for MCs in allergy and infection suggest additional drug targets to prevent the development of allergic disease and allergic exacerbations of established disease.

Authors
Hofmann, AM; Abraham, SN
MLA Citation
Hofmann, AM, and Abraham, SN. "New roles for mast cells in modulating allergic reactions and immunity against pathogens." Current opinion in immunology 21.6 (December 2009): 679-686. (Review)
PMID
19828301
Source
epmc
Published In
Current Opinion in Immunology
Volume
21
Issue
6
Publish Date
2009
Start Page
679
End Page
686
DOI
10.1016/j.coi.2009.09.007

Mast cell activator as a mucosal adjuvant in intranasal pertussis vaccine

Authors
Hofmann, AM; Staats, HF; Abraham, SN
MLA Citation
Hofmann, AM, Staats, HF, and Abraham, SN. "Mast cell activator as a mucosal adjuvant in intranasal pertussis vaccine." December 2009.
Source
wos-lite
Published In
Clinical & Experimental Allergy
Volume
39
Issue
12
Publish Date
2009
Start Page
1940
End Page
1940

Salmonella disrupts lymph node architecture by TLR4-mediated suppression of homeostatic chemokines.

We report that infection of draining lymph nodes (DLNs) by Salmonella typhimurium results in the specific downregulation of the homeostatic chemokines CCL21 and CXCL13, which are essential for normal DLN organization and function. Our data reveal that the mechanism of this suppression is dependent on S. typhimurium LPS (sLPS). The decrease in CCL21 expression involves interaction between sLPS and CCL21-producing cells within DLNs, triggering a distinct Toll-like receptor 4 (TLR4)-mediated host signaling response. In this response, suppressor of cytokine signaling-3 (Socs3) is upregulated, which negatively regulates mothers against decapentaplegic homolog-3 (Smad3)-initiated production of CCL21. Disruption of lymph node architecture and cellular trafficking enhances S. typhimurium virulence and could represent a mechanism of immune suppression used by pathogens that primarily target lymphoid tissue.

Authors
St John, AL; Abraham, SN
MLA Citation
St John, AL, and Abraham, SN. "Salmonella disrupts lymph node architecture by TLR4-mediated suppression of homeostatic chemokines." Nat Med 15.11 (November 2009): 1259-1265.
PMID
19855398
Source
pubmed
Published In
Nature Medicine
Volume
15
Issue
11
Publish Date
2009
Start Page
1259
End Page
1265
DOI
10.1038/nm.2036

The expanding roles of caveolin proteins in microbial pathogenesis.

Caveolin proteins have been implicated in a wide range of cellular functions including lipid raft mediated endocytosis and regulation of cell signaling cascades. Recent discoveries have shown that these proteins are involved not only in regulating these homeostatic cellular functions, but also in the host response to a wide range of different infections. Both caveolin-1 and 2 have been shown to play important roles in pathogen uptake. While caveolin-1 is the most well studied member of this family, a growing body of evidence has now recognized the role of caveolin-2 in these host pathogen interactions and novel host defense mechanisms.

Authors
Zaas, DW; Swan, Z; Brown, BJ; Wright, JR; Abraham, SN
MLA Citation
Zaas, DW, Swan, Z, Brown, BJ, Wright, JR, and Abraham, SN. "The expanding roles of caveolin proteins in microbial pathogenesis." Commun Integr Biol 2.6 (November 2009): 535-537.
PMID
20195460
Source
pubmed
Published In
Communicative & integrative biology
Volume
2
Issue
6
Publish Date
2009
Start Page
535
End Page
537

Mast cell-derived particles deliver peripheral signals to remote lymph nodes.

During infection, signals from the periphery are known to reach draining lymph nodes (DLNs), but how these molecules, such as inflammatory cytokines, traverse the significant distances involved without dilution or degradation remains unclear. We show that peripheral mast cells, upon activation, release stable submicrometer heparin-based particles containing tumor necrosis factor and other proteins. These complexes enter lymphatic vessels and rapidly traffic to the DLNs. This physiological drug delivery system facilitates communication between peripheral sites of inflammation and remote secondary lymphoid tissues.

Authors
Kunder, CA; St John, AL; Li, G; Leong, KW; Berwin, B; Staats, HF; Abraham, SN
MLA Citation
Kunder, CA, St John, AL, Li, G, Leong, KW, Berwin, B, Staats, HF, and Abraham, SN. "Mast cell-derived particles deliver peripheral signals to remote lymph nodes." J Exp Med 206.11 (October 26, 2009): 2455-2467.
PMID
19808250
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
206
Issue
11
Publish Date
2009
Start Page
2455
End Page
2467
DOI
10.1084/jem.20090805

Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues.

Mast cells (MCs) are best known for eliciting harmful reactions, mostly after primary immunity has been established. Here, we report that, during footpad infection with E. coli in MC-deficient mice, as compared to their MC-sufficient counterparts, the serum antibody response is significantly diminished and less protective following passive immunization in a urinary tract infection (UTI) model in wild-type mice. MCs were found to recruit large numbers of dendritic cells (DCs) into the infected tissue site, which eventually migrated into draining lymph nodes (DLNs) during a prolonged time course. This pattern of trafficking was facilitated by MC-generated TNF, which increased the expression of E-selectin on local blood vessels. Antibody blockade of E-selectin inhibited DC recruitment into the site of infection and DLNs and consequently impaired the primary humoral immune response. Thus, during infection, resident MCs contribute to the primary protective adaptive response through recruitment of DCs from the circulation into infected sites.

Authors
Shelburne, CP; Nakano, H; St John, AL; Chan, C; McLachlan, JB; Gunn, MD; Staats, HF; Abraham, SN
MLA Citation
Shelburne, CP, Nakano, H, St John, AL, Chan, C, McLachlan, JB, Gunn, MD, Staats, HF, and Abraham, SN. "Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues." Cell Host Microbe 6.4 (October 22, 2009): 331-342.
PMID
19837373
Source
pubmed
Published In
Cell Host and Microbe
Volume
6
Issue
4
Publish Date
2009
Start Page
331
End Page
342
DOI
10.1016/j.chom.2009.09.004

TLR4-mediated expulsion of bacteria from infected bladder epithelial cells.

Uropathogenic Escherichia coli invade bladder epithelial cells (BECs) by direct entry into specialized cAMP regulated exocytic compartments. Remarkably, a significant number of these intracellular bacteria are subsequently expelled in a nonlytic and piecemeal fashion by infected BECs. Here, we report that expulsion of intracellular E. coli by infected BECs is initiated by the pattern recognition receptor, Toll-like receptor (TLR)4, after activation by LPS. Also, we reveal that caveolin-1, Rab27b, PKA, and MyRIP are components of the exocytic compartment, and that they form a complex involved in the exocytosis of bacteria. This capacity of TLR4 to mediate the expulsion of intracellular bacteria from infected cells represents a previously unrecognized function for this innate immune receptor.

Authors
Song, J; Bishop, BL; Li, G; Grady, R; Stapleton, A; Abraham, SN
MLA Citation
Song, J, Bishop, BL, Li, G, Grady, R, Stapleton, A, and Abraham, SN. "TLR4-mediated expulsion of bacteria from infected bladder epithelial cells." Proc Natl Acad Sci U S A 106.35 (September 1, 2009): 14966-14971.
PMID
19706440
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
35
Publish Date
2009
Start Page
14966
End Page
14971
DOI
10.1073/pnas.0900527106

Involvement of dynamin-2 in formation of discoid vesicles in urinary bladder umbrella cells.

Umbrella cells (UCs) of the epithelium of the urinary bladder have the capacity to control bladder volume by regulating exocytosis/endocytosis of their intracellular discoid vesicles (DVs). Dynamin (Dyn) is a GTPase that promotes endocytic processes through scission of cell membranes. We have examined whether Dyn2, the most abundant Dyn form, is expressed in UCs and contributes to their endocytic actions. A specific antibody against Dyn2 was used to localize Dyn2 in human and rodent UCs by immunohistochemistry. To clarify the functional roles of Dyn2, mouse bladders were treated with a Dyn-GTPase inhibitor, dynasore, and its effects on their UC structure were assessed. Since uropathogenic Escherichia coli can be encased into UCs during infection, we used immunohistochemistry to determine whether bacteria-encasing compartments in the infected UCs were also enriched with Dyn2. Light microscopy showed that Dyn2 was abundantly expressed in UCs, especially near the apical cytoplasmic regions. By immunoelectron microscopy, Dyn2 was found on and around DV membranes in UCs. Ultrastructural analysis with a quick-freezing and deep-etching method confirmed these findings and revealed the existence of distinct Dyn2-bound microfilaments in close association with DV membranes. Dynasore treatment of bladders markedly reduced the number of DVs in UCs. In infected UCs, E. coli was encased in compartments enriched in Dyn2. Therefore, Dyn2 is highly enriched in UCs and mostly associated with membranes of DVs and microfilaments in the UCs. Pretreatment of bladders with dynasore inhibits E. coli invasion of UCs. Dyn2 thus contributes to the structural integrity of DVs and to the endocytic activity of UCs.

Authors
Terada, N; Ohno, N; Saitoh, S; Saitoh, Y; Fujii, Y; Kondo, T; Katoh, R; Chan, C; Abraham, SN; Ohno, S
MLA Citation
Terada, N, Ohno, N, Saitoh, S, Saitoh, Y, Fujii, Y, Kondo, T, Katoh, R, Chan, C, Abraham, SN, and Ohno, S. "Involvement of dynamin-2 in formation of discoid vesicles in urinary bladder umbrella cells." Cell Tissue Res 337.1 (July 2009): 91-102.
PMID
19479281
Source
pubmed
Published In
Cell and Tissue Research
Volume
337
Issue
1
Publish Date
2009
Start Page
91
End Page
102
DOI
10.1007/s00441-009-0804-z

The mast cell activator compound 48/80 is safe and effective when used as an adjuvant for intradermal immunization with Bacillus anthracis protective antigen.

We evaluated the safety and efficacy of the mast cell activator compound 48/80 (C48/80) when used as an adjuvant delivered intradermally (ID) with recombinant anthrax protective antigen (rPA) in comparison with two well-known adjuvants. Mice were vaccinated in the ear pinnae with rPA or rPA+C48/80, CpG oligodeoxynucleotides (CpG), or cholera toxin (CT). All adjuvants induced similar increases in serum anti-rPA IgG and lethal toxin neutralizing antibodies. C48/80 induced a balanced cytokine production (Th1/Th2/Th17) by antigen-restimulated splenocytes, minimal injection site inflammation, and no antigen-specific IgE. Histological analysis demonstrated that vaccination with C48/80 reduced the number of resident mast cells and induced an injection site neutrophil influx within 24h. Our data demonstrate that C48/80 is a safe and effective adjuvant, when used by the intradermal route, to induce protective antibody and balanced Th1/Th2/Th17 responses.

Authors
McGowen, AL; Hale, LP; Shelburne, CP; Abraham, SN; Staats, HF
MLA Citation
McGowen, AL, Hale, LP, Shelburne, CP, Abraham, SN, and Staats, HF. "The mast cell activator compound 48/80 is safe and effective when used as an adjuvant for intradermal immunization with Bacillus anthracis protective antigen." Vaccine 27.27 (June 2, 2009): 3544-3552.
PMID
19464533
Source
pubmed
Published In
Vaccine
Volume
27
Issue
27
Publish Date
2009
Start Page
3544
End Page
3552
DOI
10.1016/j.vaccine.2009.03.069

Counteracting signaling activities in lipid rafts associated with the invasion of lung epithelial cells by Pseudomonas aeruginosa.

Pseudomonas aeruginosa has the capacity to invade lung epithelial cells by co-opting the intrinsic endocytic properties of lipid rafts, which are rich in cholesterol, sphingolipids, and proteins, such as caveolin-1 and -2. We compared intratracheal Pseudomonas infection in wild type and caveolin-deficient mice to investigate the role of caveolin proteins in the pathogenesis of Pseudomonas pneumonia. Unlike wild type mice, which succumb to pneumonia, caveolin-deficient mice are resistant to Pseudomonas. We observed that Pseudomonas invasion of lung epithelial cells is dependent on caveolin-2 but not caveolin-1. Phosphorylation of caveolin-2 by Src family kinases is an essential event for Pseudomonas invasion. Our studies also reveal the existence of a distinct signaling mechanism in lung epithelial cells mediated by COOH-terminal Src kinase (Csk) that negatively regulates Pseudomonas invasion. Csk migrates to lipid raft domains, where it decreases phosphorylation of caveolin-2 by inactivating c-Src. Whereas Pseudomonas co-opts the endocytic properties of caveolin-2 for invasion, there also exists in these cells an intrinsic Csk-dependent cellular defense mechanism aimed at impairing this activity. The success of Pseudomonas in co-opting lipid raft-mediated endocytosis to invade lung epithelial cells may depend on the relative strengths of these counteracting signaling activities.

Authors
Zaas, DW; Swan, ZD; Brown, BJ; Li, G; Randell, SH; Degan, S; Sunday, ME; Wright, JR; Abraham, SN
MLA Citation
Zaas, DW, Swan, ZD, Brown, BJ, Li, G, Randell, SH, Degan, S, Sunday, ME, Wright, JR, and Abraham, SN. "Counteracting signaling activities in lipid rafts associated with the invasion of lung epithelial cells by Pseudomonas aeruginosa." J Biol Chem 284.15 (April 10, 2009): 9955-9964.
PMID
19211560
Source
pubmed
Published In
The Journal of biological chemistry
Volume
284
Issue
15
Publish Date
2009
Start Page
9955
End Page
9964
DOI
10.1074/jbc.M808629200

Use of a Mast Cell Activator as a Mucosal Adjuvant for Pertussis Vaccines

Authors
Hofmann, AM; Staats, HF; Abraham, SN
MLA Citation
Hofmann, AM, Staats, HF, and Abraham, SN. "Use of a Mast Cell Activator as a Mucosal Adjuvant for Pertussis Vaccines." JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 123.2 (February 2009): S164-S164.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
123
Issue
2
Publish Date
2009
Start Page
S164
End Page
S164
DOI
10.1016/j.jaci.2008.12.618

Involvement of dynamin-2 in formation of discoid vesicles in urinary bladder umbrella cells

Umbrella cells (UCs) of the epithelium of the urinary bladder have the capacity to control bladder volume by regulating exocytosis/endocytosis of their intracellular discoid vesicles (DVs). Dynamin (Dyn) is a GTPase that promotes endocytic processes through scission of cell membranes. We have examined whether Dyn2, the most abundant Dyn form, is expressed in UCs and contributes to their endocytic actions. A specific antibody against Dyn2 was used to localize Dyn2 in human and rodent UCs by immunohistochemistry. To clarify the functional roles of Dyn2, mouse bladders were treated with a Dyn-GTPase inhibitor, dynasore, and its effects on their UC structure were assessed. Since uropathogenic Escherichia coli can be encased into UCs during infection, we used immunohistochemistry to determine whether bacteria-encasing compartments in the infected UCs were also enriched with Dyn2. Light microscopy showed that Dyn2 was abundantly expressed in UCs, especially near the apical cytoplasmic regions. By immunoelectron microscopy, Dyn2 was found on and around DV membranes in UCs. Ultrastructural analysis with a quick-freezing and deep-etching method confirmed these findings and revealed the existence of distinct Dyn2-bound microfilaments in close association with DV membranes. Dynasore treatment of bladders markedly reduced the number of DVs in UCs. In infected UCs, E. coli was encased in compartments enriched in Dyn2. Therefore, Dyn2 is highly enriched in UCs and mostly associated with membranes of DVs and microfilaments in the UCs. Pretreatment of bladders with dynasore inhibits E. coli invasion of UCs. Dyn2 thus contributes to the structural integrity of DVs and to the endocytic activity of UCs. © 2009 Springer-Verlag.

Authors
Terada, N; Ohno, N; Saitoh, S; Saitoh, Y; Fujii, Y; Kondo, T; Katoh, R; Chan, C; Abraham, SN; Ohno, S
MLA Citation
Terada, N, Ohno, N, Saitoh, S, Saitoh, Y, Fujii, Y, Kondo, T, Katoh, R, Chan, C, Abraham, SN, and Ohno, S. "Involvement of dynamin-2 in formation of discoid vesicles in urinary bladder umbrella cells." Cell and Tissue Research (2009): 1-12.
Source
scival
Published In
Cell and Tissue Research
Publish Date
2009
Start Page
1
End Page
12
DOI
10.1007/s00441-009-0804-z

AHR Is Attenuated in Caveolin-1 Deficient Mice

Authors
Brown, BJ; Pastva, AM; Lo, B; Foster, WM; Eu, P; Que, LG; Abraham, SN; Wright, JR; Zaas, DW
MLA Citation
Brown, BJ, Pastva, AM, Lo, B, Foster, WM, Eu, P, Que, LG, Abraham, SN, Wright, JR, and Zaas, DW. "AHR Is Attenuated in Caveolin-1 Deficient Mice." AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 179 (2009).
Source
wos-lite
Published In
American journal of respiratory and critical care medicine
Volume
179
Publish Date
2009

Mast Cells Are Required for the Development of Allograft Rejection in a Murine Model of Obliterative Bronchiolitis

Authors
Zaas, DW; Swan, ZD; Randell, SH; Wright, JR; Palmer, SM; Abraham, SN
MLA Citation
Zaas, DW, Swan, ZD, Randell, SH, Wright, JR, Palmer, SM, and Abraham, SN. "Mast Cells Are Required for the Development of Allograft Rejection in a Murine Model of Obliterative Bronchiolitis." AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 179 (2009).
Source
wos-lite
Published In
American journal of respiratory and critical care medicine
Volume
179
Publish Date
2009

Innate and adaptive immune responses in the urinary tract.

As new and intriguing details of how uropathogens initiate infections and persist within the urinary tract have emerged, so has important information regarding how the immune system functions within the urinary tract. Recent studies have revealed the existence of a multifaceted innate immune response triggered by Toll-like receptor (TLR) 4 on superficial bladder epithelial cells directed at clearing infection by Gram negative pathogens. Other studies have reported that the adaptive immune response in the urinary tract is effective and that vaccines comprised of bacterial virulence factors or whole dead bacteria can evoke protective immunity against urinary tract infections (UTIs) in animals and humans. As antibiotic therapy becomes increasingly ineffective, modulating the innate and adaptive immune system in the urinary tract using TLR4 ligands and other immunomodulators may become viable options to combat UTIs.

Authors
Song, J; Abraham, SN
MLA Citation
Song, J, and Abraham, SN. "Innate and adaptive immune responses in the urinary tract." Eur J Clin Invest 38 Suppl 2 (October 2008): 21-28. (Review)
PMID
18826478
Source
pubmed
Published In
European Journal of Clinical Investigation
Volume
38 Suppl 2
Publish Date
2008
Start Page
21
End Page
28
DOI
10.1111/j.1365-2362.2008.02005.x

Mast cell activators: a new class of highly effective vaccine adjuvants.

Mast cells (MCs) have recently received recognition as prominent effectors in the regulation of immune cell migration to draining lymph nodes and lymphocyte activation. However, their role in the development of humoral immune responses is not clear. Here, we demonstrate that subcutaneous or nasal administration of small-molecule MC activators with vaccine antigens evokes large increases in antigen-specific serum immunoglobulin G (IgG) responses. These responses were MC dependent and correlated with increased dendritic cell and lymphocyte recruitment to draining lymph nodes. Nasal instillation of these formulations also evoked antigen-specific secretory IgA and provided protection against anthrax lethal toxin challenge in vitro and against vaccinia virus infection in vivo. Collectively, these results define the MC as an integral sensory arm of the adaptive immune system. Moreover, they highlight MC activators as a new class of vaccine adjuvants, capable of inducing protective antigen-specific immune responses through needle-free routes of administration.

Authors
McLachlan, JB; Shelburne, CP; Hart, JP; Pizzo, SV; Goyal, R; Brooking-Dixon, R; Staats, HF; Abraham, SN
MLA Citation
McLachlan, JB, Shelburne, CP, Hart, JP, Pizzo, SV, Goyal, R, Brooking-Dixon, R, Staats, HF, and Abraham, SN. "Mast cell activators: a new class of highly effective vaccine adjuvants." Nat Med 14.5 (May 2008): 536-541.
PMID
18425129
Source
pubmed
Published In
Nature Medicine
Volume
14
Issue
5
Publish Date
2008
Start Page
536
End Page
541
DOI
10.1038/nm1757

TLR-mediated immune responses in the urinary tract.

The urinary tract is one of the most intractable mucosal surfaces for pathogens to colonize. In addition to the natural barriers at this site, potential pathogens have to contend with the vigorous local innate immune system. Several Toll-like receptors (TLRs) have been identified on epithelial cells of the bladder and the kidneys which mediate a variety of powerful immune responses. A common finding among successful uropathogens is their intrinsic ability to suppress TLR-mediated responses. As antibiotic therapy becomes increasingly ineffective, employing boosters of the innate immune system in the urinary tract may become a viable option.

Authors
Song, J; Abraham, SN
MLA Citation
Song, J, and Abraham, SN. "TLR-mediated immune responses in the urinary tract." Curr Opin Microbiol 11.1 (February 2008): 66-73. (Review)
PMID
18243043
Source
pubmed
Published In
Current Opinion in Microbiology
Volume
11
Issue
1
Publish Date
2008
Start Page
66
End Page
73
DOI
10.1016/j.mib.2007.12.001

TLR4-initiated and cAMP-mediated abrogation of bacterial invasion of the bladder.

The remarkable resistance of the urinary tract to infection has been attributed to its physical properties and the innate immune responses triggered by pattern recognition receptors lining the tract. We report a distinct TLR4 mediated mechanism in bladder epithelial cells (BECs) that abrogates bacterial invasion, a necessary step for successful infection. Compared to controls, uropathogenic type 1 fimbriated Escherichia coli and Klebsiella pneumoniae invaded BECs of TLR4 mutant mice in 10-fold or greater numbers. TLR4 mediated suppression of bacterial invasion was linked to increased intracellular cAMP levels which negatively impacted Rac-1 mediated mobilization of the cytoskeleton. Artificially increasing intracellular cAMP levels in BECs of TLR4 mutant mice restored resistance to type 1 fimbriated bacterial invasion. This finding reveals a novel function for TLR4 and another facet of bladder innate defense.

Authors
Song, J; Bishop, BL; Li, G; Duncan, MJ; Abraham, SN
MLA Citation
Song, J, Bishop, BL, Li, G, Duncan, MJ, and Abraham, SN. "TLR4-initiated and cAMP-mediated abrogation of bacterial invasion of the bladder." Cell Host Microbe 1.4 (June 14, 2007): 287-298.
PMID
17710226
Source
pubmed
Published In
Cell Host and Microbe
Volume
1
Issue
4
Publish Date
2007
Start Page
287
End Page
298
DOI
10.1016/j.chom.2007.05.007

Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells.

The superficial bladder epithelium is a powerful barrier to urine and also serves as a regulator of bladder volume, which is achieved by apical exocytosis of specialized fusiform vesicles during distension of the bladder. We report that type 1 fimbriated uropathogenic Escherichia coli (UPEC) circumvents the bladder barrier by harboring in these Rab27b/CD63-positive and cAMP-regulatable fusiform vesicles within bladder epithelial cells (BECs). Incorporation of UPEC into BEC fusiform compartments enabled bacteria to escape elimination during voiding and to re-emerge in the urine as the bladder distended. Notably, treatment of UPEC-infected mice with a drug that increases intracellular cAMP and induces exocytosis of fusiform vesicles reduced the number of intracellular E. coli.

Authors
Bishop, BL; Duncan, MJ; Song, J; Li, G; Zaas, D; Abraham, SN
MLA Citation
Bishop, BL, Duncan, MJ, Song, J, Li, G, Zaas, D, and Abraham, SN. "Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells." Nat Med 13.5 (May 2007): 625-630.
PMID
17417648
Source
pubmed
Published In
Nature Medicine
Volume
13
Issue
5
Publish Date
2007
Start Page
625
End Page
630
DOI
10.1038/nm1572

Mast cells enable heightened humoral immunity during infection

Authors
Shelburne, CP; St John, A; McLachlau, JB; Staats, HF; Abraham, SN
MLA Citation
Shelburne, CP, St John, A, McLachlau, JB, Staats, HF, and Abraham, SN. "Mast cells enable heightened humoral immunity during infection." JOURNAL OF IMMUNOLOGY 178 (April 1, 2007).
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
178
Publish Date
2007

The mast cell activator Compound 48/80 is a potent adjuvant for intradermally-administered anthrax protective antigen

Authors
McGowen, A; Paraggio, NA; Sobel, AE; Kirwan, SM; Shelburne, CP; Pizzo, SV; Abraham, SN; Staats, HF
MLA Citation
McGowen, A, Paraggio, NA, Sobel, AE, Kirwan, SM, Shelburne, CP, Pizzo, SV, Abraham, SN, and Staats, HF. "The mast cell activator Compound 48/80 is a potent adjuvant for intradermally-administered anthrax protective antigen." JOURNAL OF IMMUNOLOGY 178 (April 1, 2007).
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
178
Publish Date
2007

A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells.

The vigorous cytokine response of immune cells to Gram-negative bacteria is primarily mediated by a recognition molecule, Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharide (LPS) and initiates a series of intracellular NF-kappaB-associated signaling events. Recently, bladder epithelial cells (BECs) were reported to express TLR4 and to evoke a vigorous cytokine response upon exposure to LPS. We examined intracellular signaling events in human BECs leading to the production of IL-6, a major urinary cytokine, following activation by Escherichia coli and isolated LPS. We observed that in addition to the classical NF-kappaB-associated pathway, TLR4 triggers a distinct and more rapid signaling response involving, sequentially, Ca(2+), adenylyl cyclase 3-generated cAMP, and a transcriptional factor, cAMP response element-binding protein. This capacity of BECs to mobilize secondary messengers and evoke a more rapid IL-6 response might be critical in their role as first responders to microbial challenge in the urinary tract.

Authors
Song, J; Duncan, MJ; Li, G; Chan, C; Grady, R; Stapleton, A; Abraham, SN
MLA Citation
Song, J, Duncan, MJ, Li, G, Chan, C, Grady, R, Stapleton, A, and Abraham, SN. "A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells." PLoS Pathog 3.4 (April 2007): e60-.
PMID
17465679
Source
pubmed
Published In
PLoS pathogens
Volume
3
Issue
4
Publish Date
2007
Start Page
e60
DOI
10.1371/journal.ppat.0030060

Attenuated virulence of a Francisella mutant lacking the lipid A 4'-phosphatase.

Francisella tularensis causes tularemia, a highly contagious disease of animals and humans, but the virulence features of F. tularensis are poorly defined. F. tularensis and the related mouse pathogen Francisella novicida synthesize unusual lipid A molecules lacking the 4'-monophosphate group typically found in the lipid A of Gram-negative bacteria. LpxF, a selective phosphatase located on the periplasmic surface of the inner membrane, removes the 4'-phosphate moiety in the late stages of F. novicida lipid A assembly. To evaluate the relevance of the 4'-phosphatase to pathogenesis, we constructed a deletion mutant of lpxF and compared its virulence with wild-type F. novicida. Intradermal injection of 10(6) wild-type but not 10(8) mutant F. novicida cells is lethal to mice. The rapid clearance of the lpxF mutant is associated with a stronger local cytokine response and a greater influx of neutrophils compared with wild-type. The F. novicida mutant was highly susceptible to the cationic antimicrobial peptide polymyxin. LpxF therefore represents a kind of virulence factor that confers a distinct lipid A phenotype, preventing Francisella from activating the host innate immune response and preventing the bactericidal actions of cationic peptides. Francisella lpxF mutants may be useful for immunization against tularemia.

Authors
Wang, X; Ribeiro, AA; Guan, Z; Abraham, SN; Raetz, CRH
MLA Citation
Wang, X, Ribeiro, AA, Guan, Z, Abraham, SN, and Raetz, CRH. "Attenuated virulence of a Francisella mutant lacking the lipid A 4'-phosphatase." Proc Natl Acad Sci U S A 104.10 (March 6, 2007): 4136-4141.
PMID
17360489
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
104
Issue
10
Publish Date
2007
Start Page
4136
End Page
4141
DOI
10.1073/pnas.0611606104

A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells.

The vigorous cytokine response of immune cells to Gram-negative bacteria is primarily mediated by a recognition molecule, Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharide (LPS) and initiates a series of intracellular NF-kappaB-associated signaling events. Recently, bladder epithelial cells (BECs) were reported to express TLR4 and to evoke a vigorous cytokine response upon exposure to LPS. We examined intracellular signaling events in human BECs leading to the production of IL-6, a major urinary cytokine, following activation by Escherichia coli and isolated LPS. We observed that in addition to the classical NF-kappaB-associated pathway, TLR4 triggers a distinct and more rapid signaling response involving, sequentially, Ca(2+), adenylyl cyclase 3-generated cAMP, and a transcriptional factor, cAMP response element-binding protein. This capacity of BECs to mobilize secondary messengers and evoke a more rapid IL-6 response might be critical in their role as first responders to microbial challenge in the urinary tract.

Authors
Song, J; Duncan, MJ; Li, G; Chan, C; Grady, R; Stapleton, A; Abraham, SN
MLA Citation
Song, J, Duncan, MJ, Li, G, Chan, C, Grady, R, Stapleton, A, and Abraham, SN. "A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells." PLoS pathogens 3.4 (2007): e60-.
Source
scival
Published In
PLoS pathogens
Volume
3
Issue
4
Publish Date
2007
Start Page
e60
DOI
10.1371/journal.ppat.0030060

Harboring of particulate allergens within secretory compartments by mast cells following IgE/FcepsilonRI-lipid raft-mediated phagocytosis.

Although much is known regarding the exocytic responses of mast cells following allergen/IgE-mediated activation, little is currently known of the fate of the activating allergens, many of which are particles. We have found that IgE-bound particulate allergens were phagocytosed by activated mast cells in a lipid raft-dependent manner. The nascent allergen-containing phagosomes were found to transform into granule compartments by acquiring VAMP7 and serotonin and exhibited the capacity to empty their contents upon mast cell activation. When allergen-harboring mast cells were stimulated, the intracellular allergens were expelled intact and shown to activate adjacent mast cells. This capacity of mast cells to phagocytose and retain whole and antigenically intact allergens could potentially contribute to the course of inflammatory diseases such as asthma.

Authors
Shin, J-S; Shelburne, CP; Jin, C; LeFurgey, EA; Abraham, SN
MLA Citation
Shin, J-S, Shelburne, CP, Jin, C, LeFurgey, EA, and Abraham, SN. "Harboring of particulate allergens within secretory compartments by mast cells following IgE/FcepsilonRI-lipid raft-mediated phagocytosis." J Immunol 177.9 (November 1, 2006): 5791-5800.
PMID
17056503
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
177
Issue
9
Publish Date
2006
Start Page
5791
End Page
5800

Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production.

The fungal secondary metabolite gliotoxin produced by Aspergillus fumigatus has been hypothesized to be important in the development of invasive aspergillosis. In this study, we addressed this hypothesis by disrupting a nonribosomal peptide synthetase (NRPS) (encoded by gliP) predicted to be involved in gliotoxin production. Mutants with a disrupted gliP locus failed to produce gliotoxin, which confirmed the role of the NRPS encoded by gliP in gliotoxin biosynthesis. We found no morphological, developmental, or physiological defects in DeltagliP mutant strains. In addition, disruption of gliP resulted in down regulation of gene expression in the gliotoxin biosynthesis gene cluster, which was restored with addition of exogenous gliotoxin. This interesting result suggests a role for gliotoxin in regulating its own production. Culture filtrates from the DeltagliP mutant were unable to inhibit ionomycin-dependent degranulation of mast cells, suggesting a role for gliotoxin in suppressing mast cell degranulation and possibly in disease development. However, the DeltagliP mutant did not have an impact on survival or tissue burden in a murine inhalational model of invasive aspergillosis. This result suggests that gliotoxin is not required for virulence in an immunosuppressed host with an invasive pulmonary infection.

Authors
Cramer, RA; Gamcsik, MP; Brooking, RM; Najvar, LK; Kirkpatrick, WR; Patterson, TF; Balibar, CJ; Graybill, JR; Perfect, JR; Abraham, SN; Steinbach, WJ
MLA Citation
Cramer, RA, Gamcsik, MP, Brooking, RM, Najvar, LK, Kirkpatrick, WR, Patterson, TF, Balibar, CJ, Graybill, JR, Perfect, JR, Abraham, SN, and Steinbach, WJ. "Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production." Eukaryot Cell 5.6 (June 2006): 972-980.
PMID
16757745
Source
pubmed
Published In
Eukaryotic cell
Volume
5
Issue
6
Publish Date
2006
Start Page
972
End Page
980
DOI
10.1128/EC.00049-06

In vivo models for studying mast cell-dependent responses to bacterial infection.

Mast cells are a critical component of host defense against bacterial infections. Activation of these cells during infection induces both innate and adaptive aspects of protective immunity needed for the elimination of the bacteria and survival of the host. These functional roles for the mast cell have been principally characterized using two in vivo models of acute bacterial infection featuring Gram-negative pathogens such as Escherichia coli. Here, we present basic protocols for the identification of mast cell-dependent biological functions during bacterial infection. These include the use of mast cell-deficient mice, the identification of mast cells in tissue, the culture of uropathogenic E. coli, and the basic analysis of mast cell-dependent functions in the peritoneal cavity and footpad models of bacterial pathogenesis.

Authors
Shelburne, CP; McLachlan, JB; Abraham, SN
MLA Citation
Shelburne, CP, McLachlan, JB, and Abraham, SN. "In vivo models for studying mast cell-dependent responses to bacterial infection." Methods Mol Biol 315 (2006): 363-381.
PMID
16110170
Source
pubmed
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
315
Publish Date
2006
Start Page
363
End Page
381

The role of lipid rafts in the pathogenesis of bacterial infections.

Numerous pathogens have evolved mechanisms of co-opting normal host endocytic machinery as a means of invading host cells. While numerous pathogens have been known to enter cells via traditional clathrin-coated pit endocytosis, a growing number of viral and bacterial pathogens have been recognized to invade host cells via clustered lipid rafts. This review focuses on several bacterial pathogens that have evolved several different mechanisms of co-opting clustered lipid rafts to invade host cells. Although these bacteria have diverse clinical presentations and many differences in their pathogenesis, they each depend on the integrity of clustered lipid rafts for their intracellular survival. Bacterial invasion via clustered lipid rafts has been recognized as an important virulence factor for a growing number of bacterial pathogens in their battle against host defenses.

Authors
Zaas, DW; Duncan, M; Rae Wright, J; Abraham, SN
MLA Citation
Zaas, DW, Duncan, M, Rae Wright, J, and Abraham, SN. "The role of lipid rafts in the pathogenesis of bacterial infections." Biochim Biophys Acta 1746.3 (December 30, 2005): 305-313. (Review)
PMID
16289370
Source
pubmed
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
1746
Issue
3
Publish Date
2005
Start Page
305
End Page
313
DOI
10.1016/j.bbamcr.2005.10.003

The distinct binding specificities exhibited by enterobacterial type 1 fimbriae are determined by their fimbrial shafts.

Type 1 fimbriae of enterobacteria are heteropolymeric organelles of adhesion composed of FimH, a mannose-binding lectin, and a shaft composed primarily of FimA. We compared the binding activities of recombinant clones expressing type 1 fimbriae from Escherichia coli, Klebsiella pneumoniae, and Salmonella typhimurium for gut and uroepithelial cells and for various soluble mannosylated proteins. Each fimbria was characterized by its capacity to bind particular epithelial cells and to aggregate mannoproteins. However, when each respective FimH subunit was cloned and expressed in the absence of its shaft as a fusion protein with MalE, each FimH bound a wide range of mannose-containing compounds. In addition, we found that expression of FimH on a heterologous fimbrial shaft, e.g. K. pneumoniae FimH on the E. coli fimbrial shaft or vice versa, altered the binding specificity of FimH such that it closely resembled that of the native heterologous type 1 fimbriae. Furthermore, attachment to and invasion of bladder epithelial cells, which were mediated much better by native E. coli type 1 fimbriae compared with native K. pneumoniae type 1 fimbriae, were found to be dependent on the background of the fimbrial shaft (E. coli versus K. pneumoniae) rather than the background of the FimH expressed. Thus, the distinct binding specificities of different enterobacterial type 1 fimbriae cannot be ascribed solely to the primary structure of their respective FimH subunits, but are also modulated by the fimbrial shaft on which each FimH subunit is presented, possibly through conformational constraints imposed on FimH by the fimbrial shaft. The capacity of type 1 fimbrial shafts to modulate the tissue tropism of different enterobacterial species represents a novel function for these highly organized structures.

Authors
Duncan, MJ; Mann, EL; Cohen, MS; Ofek, I; Sharon, N; Abraham, SN
MLA Citation
Duncan, MJ, Mann, EL, Cohen, MS, Ofek, I, Sharon, N, and Abraham, SN. "The distinct binding specificities exhibited by enterobacterial type 1 fimbriae are determined by their fimbrial shafts." J Biol Chem 280.45 (November 11, 2005): 37707-37716.
PMID
16118220
Source
pubmed
Published In
The Journal of biological chemistry
Volume
280
Issue
45
Publish Date
2005
Start Page
37707
End Page
37716
DOI
10.1074/jbc.M501249200

Surfactant protein D decreases pollen-induced IgE-dependent mast cell degranulation.

Mast cells play a key role in allergy and asthma. They reside at the host-environment interface and are among the first cells to make contact with inhaled microorganisms and particulate antigens. Pulmonary surfactant proteins A and D (SP-A and SP-D) function in lung host defense by enhancing microbe phagocytosis and mediating other immune cell functions, but little is known about their effects on mast cells. We hypothesized that SP-A and/or SP-D modulate IgE-dependent mast cell functions. Pollen starch granules (PSG) extracted from Dactylis glomerata and coated with trinitrophenol (TNP) were used as a model of an inhaled organic particulate allergen. Our data revealed that SP-D inhibited by 50% the release of beta-hexosaminidase by peritoneal mast cells sensitized with IgE anti-TNP and stimulated with TNP-PSG. In contrast, SP-A had no effect. Furthermore, SP-D aggregated PSG in a dose-dependent manner, and this aggregation was mediated by SP-D's carbohydrate recognition domain. A single arm SP-D mutant (RrSP-Dser15,20) neither aggregated PSG nor inhibited degranulation, suggesting that multimerization of SP-D is required for maximal PSG aggregation and inhibition of PSG-induced mast cell degranulation. This study is the first to demonstrate that SP-D modulates IgE-mediated mast cell functions, which are important in asthma and allergic inflammation.

Authors
Malherbe, DC; Erpenbeck, VJ; Abraham, SN; Crouch, EC; Hohlfeld, JM; Wright, JR
MLA Citation
Malherbe, DC, Erpenbeck, VJ, Abraham, SN, Crouch, EC, Hohlfeld, JM, and Wright, JR. "Surfactant protein D decreases pollen-induced IgE-dependent mast cell degranulation." Am J Physiol Lung Cell Mol Physiol 289.5 (November 2005): L856-L866.
PMID
15980037
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
289
Issue
5
Publish Date
2005
Start Page
L856
End Page
L866
DOI
10.1152/ajplung.00009.2005

Bacterial penetration of the mucosal barrier by targeting lipid rafts.

Several traditionally extracellular pathogens not known to possess invasive capacity have been shown to invade various mucosal epithelial cells. The mucosal epithelium performs an important barrier function and is not typically amenable to bacterial invasion. Valuable clues to the underlying basis for bacterial invasion have emerged from recent studies examining the invasion of bladder epithelial cells by uropathogenic Escherichia coli and alveolar epithelial cells by Pseudomonas aeruginosa. In both cases, bacterial invasion is achieved through targeting of molecules specifically found within distinct glycosphingolipid- and cholesterol-enriched microdomains called lipid rafts. The importance of lipid rafts in promoting bacterial invasion was shown as disruptors of lipid rafts blocked cellular invasion by both E. coli and P. aeruginosa. In addition, molecular components of lipid rafts were found to be highly enriched in membranes encasing these intracellular bacteria. Furthermore, caveolin proteins, which serve to stabilize and organize lipid raft components, are necessary for bacterial entry. Taken together, targeting of lipid rafts appears to be an effective but poorly recognized mechanism used by pathogenic bacteria to circumvent the mucosal barriers of the host.

Authors
Abraham, SN; Duncan, MJ; Li, G; Zaas, D
MLA Citation
Abraham, SN, Duncan, MJ, Li, G, and Zaas, D. "Bacterial penetration of the mucosal barrier by targeting lipid rafts." J Investig Med 53.6 (September 2005): 318-321. (Review)
PMID
16207470
Source
pubmed
Published In
Journal of Investigative Medicine
Volume
53
Issue
6
Publish Date
2005
Start Page
318
End Page
321
DOI
10.2310/6650.2005.53609

Pseudomonas invasion of type I pneumocytes is dependent on the expression and phosphorylation of caveolin-2.

Pseudomonas aeruginosa is a major cause of pneumonia in patients with cystic fibrosis and other immuncompromising conditions. Here we showed that P. aeruginosa invades type I pneumocytes via a lipid raft-mediated mechanism. P. aeruginosa invasion of rat primary type I-like pneumocytes as well as a murine lung epithelial cell line 12 (MLE-12) is inhibited by drugs that remove membrane cholesterol and disrupt lipid rafts. Confocal microscopy demonstrated co-localization of intracellular P. aeruginosa with lipid raft components including caveolin-1 and -2. We generated caveolin-1 and -2 knockdowns in MLE-12 cells by using RNA interference techniques. Decreased expression of caveolin-2 significantly impaired the ability of P. aeruginosa to invade MLE-12 cells. In addition, the lipid raft-dependent tyrosine phosphorylation of caveolin-2 appeared to be a critical regulator of P. aeruginosa invasion.

Authors
Zaas, DW; Duncan, MJ; Li, G; Wright, JR; Abraham, SN
MLA Citation
Zaas, DW, Duncan, MJ, Li, G, Wright, JR, and Abraham, SN. "Pseudomonas invasion of type I pneumocytes is dependent on the expression and phosphorylation of caveolin-2." J Biol Chem 280.6 (February 11, 2005): 4864-4872.
PMID
15545264
Source
pubmed
Published In
The Journal of biological chemistry
Volume
280
Issue
6
Publish Date
2005
Start Page
4864
End Page
4872
DOI
10.1074/jbc.M411702200

Chapter 4 Lipid Raft-Mediated Entry of Bacteria into Host Cells

Many bacterial pathogens are known to enter into host cells, either as a means of avoiding the host immune system or as an integral part of their replicative cycle. One major hurdle intracellular pathogens must overcome is degradation in the classical endosomal/lysosomal fusion pathway. Some pathogens avoid this by escaping from their phagosomes before lysosomal fusion occurs, others actively modify their compartment to prevent lysosomal fusion, while still others have evolved defenses that allow them to survive in the harsh lysosomal environment (Small et al., 1994). Recent work has demonstrated that some pathogens have evolved a means of entering cells in a way that completely sidesteps the endosomal/lysosomal pathway altogether by utilizing discrete plasma membrane microdomains located on the host cell surface. These microdomains, commonly referred to as caveolae or lipid rafts, are enriched in cholesterol, glycosphingolipids, and glycosylphosphatidylinosotol (GPI)-anchored molecules (Anderson, 1998; Kurzchalia and Parton, 1999). Caveolae were initially described as cave-like invaginations of the plasma membrane, 50-100 nm in diameter, which contained a distinctive protein, caveolin. Since the protein caveolin is not found in all microdomains with the biochemical properties of caveolae, and not all domains with these properties have the distinctive shape of caveolae, we will define caveolae as pleomorphic lateral assemblies containing the protein caveolin-1 that are enriched in cholesterol, glycosphingolipids, and GPI-anchored molecules and that have the distinct morphological appearance of cave-like invaginations by electron microscopy (EM). Microdomains with the same biochemical properties that do not exhibit the cave-like structure of caveolae will be referred to as lipid rafts, regardless of the presence or absence of caveolin-1 within these microdomains (Harder and Simons, 1997; Simons and Ikonen, 1997; Kurzchalia and Parton, 1999). For ease of reading, except when it is necessary to make a clear distinction between caveolae and lipid rafts, the term lipid raft will be used. Most of the microbes that are utilizing lipid rafts for entry into cells bind distinct receptors on the host cell surface, which could lead one to envision multiple endocytic mechanisms for the various microbes. Another explanation for this conserved mechanism of entry is that the various receptors can all lead to the same endocytic pathway. This would imply that the various microbial receptors are located within lipid rafts or move into lipid rafts after microbial contact, as has been found to be the case for the receptors of many of the microbes and bacterial toxins that use lipid rafts (Lencer et al., 1999; Shin et al., 2000; Duncan et al., 2004). Many different signaling molecules are concentrated within lipid rafts (Anderson, 1998; Okamoto et al., 1998), including all the machinery necessary for vesicle budding, docking, and fusion (Schnitzer et al., 1995), making this an ideal pathway for microbial entry. Lipid rafts also seem to be linked to the actin cytoskeleton based on the localization of actin mobilizing/modulating molecules to lipid rafts and the recent report that the F-actin cross-linking protein filamin is a ligand for the protein caveolin-1 (Rozelle et al., 2000; Stahlhut and van Deurs, 2000). The idea that such vastly different bacterial pathogens such as FimH-expressing Escherichia coli (Baorto et al., 1997; Shin et al., 2000; Duncan et al., 2004), Salmonella typhimurium (Catron et al., 2002; Garner et al., 2002), and Chlamydia trachomatis (Norkin et al., 2001) can gain entry into host cells through a pathway involving lipid rafts, or use these structures to aid in intracellular survival, could be thought to indicate a high degree of similarity in their mechanism of entry. The fact that FimH-expressing E. coli and the infectious form of C. trachomatis (the metabolically inert elementary body) enter in a passive manner while S. typhimurium enters by actively secreting effector proteins into the cytoplasm of the host cell via a type III secretion system, thereby inducing uptake (Collazo and Galan, 1997; Suarez and Russmann, 1998), indicates that, though similarities in their mechanism of entry exist, there are distinct differences as well. Regardless, it is becoming clear that several pathogenic bacteria have recognized the endocytic functions of lipid rafts as a means of gaining entry into host cells in a manner that aids in the avoidance of lysosomal fusion and have evolved to fully exploit this mechanism of entry. © 2005 Elsevier Inc. All rights reserved.

Authors
Duncan, MJ; Abraham, SN
MLA Citation
Duncan, MJ, and Abraham, SN. "Chapter 4 Lipid Raft-Mediated Entry of Bacteria into Host Cells." Advances in Molecular and Cell Biology 36 (2005): 79-88.
Source
scival
Published In
Advances in Molecular and Cell Biology
Volume
36
Publish Date
2005
Start Page
79
End Page
88
DOI
10.1016/S1569-2558(05)36004-8

Adhesion of bacteria to mucosal surfaces

This chapter discusses about bacterial adhesions and their mucosal cell receptors. It also discusses selected postadhesion events and describes how they influence mucosal colonization. The specific binding interaction between the bacterial adhesions and host receptors allows the bacteria to firmly attach to particular sites on the mucosal surfaces and thereby resist dislocation by the hydrokinetic forces that typically act on these surfaces. Adhesion of bacteria to mucosal surfaces is an important determinant of the mucosal colonization-especially in determining its site and density. Several critical postadhesion events are necessary for the bacteria to successfully establish themselves on the mucosal surfaces and to initiate infection. These events include: alterations to the expression of virulence factors by bacteria and induction of physiologic changes on the mucosal surface. The advantages of inhibiting adhesion to prevent the bacterial colonization of mucosal surfaces rely on the assumption that the spread of strains with genotypic resistance to the methods applied are much slower than in the case of employing approaches aimed at killing the organisms. © 2005 Elsevier Inc. All rights reserved.

Authors
Abraham, SN; Bishop, BL; Sharon, N; Ofek, I
MLA Citation
Abraham, SN, Bishop, BL, Sharon, N, and Ofek, I. "Adhesion of bacteria to mucosal surfaces." Mucosal Immunology, Two-Volume Set (2005): 35-48.
Source
scival
Published In
Mucosal Immunology, Two-Volume Set
Publish Date
2005
Start Page
35
End Page
48
DOI
10.1016/B978-012491543-5/50007-3

Bacterial penetration of bladder epithelium through lipid rafts.

Type 1 fimbriated Escherichia coli represents the most common human uropathogen, owing much of its virulence to invasion of the uroepithelium, which is highly impermeable due to the preponderance of uroplakins and highly ordered lipid components. We sought to elucidate the molecular basis for E. coli invasion of the bladder epithelium by employing human 5637 bladder epithelial cells, and we found the following: (i) intracellular E. coli associated with caveolae and lipid raft components; (ii) RNA(i) reduction of caveolin-1 expression inhibited bacterial invasion; (iii) a signaling molecule required for E. coli invasion was located in lipid rafts and physically associated with caveolin-1; (iv) bacterial invasion was inhibited by lipid raft disrupting/usurping agents. In the mouse bladder, the E. coli type 1 fimbrial receptor, uroplakin Ia, was located in lipid rafts, and lipid raft disruptors inhibited E. coli invasion. Cumulatively, E. coli uroepithelial invasion occurs through lipid rafts, which, paradoxically, contribute to bladder impermeability.

Authors
Duncan, MJ; Li, G; Shin, J-S; Carson, JL; Abraham, SN
MLA Citation
Duncan, MJ, Li, G, Shin, J-S, Carson, JL, and Abraham, SN. "Bacterial penetration of bladder epithelium through lipid rafts." J Biol Chem 279.18 (April 30, 2004): 18944-18951.
PMID
14976212
Source
pubmed
Published In
The Journal of biological chemistry
Volume
279
Issue
18
Publish Date
2004
Start Page
18944
End Page
18951
DOI
10.1074/jbc.M400769200

Contribution of mast cells to bacterial clearance and their proliferation during experimental cystitis induced by type 1 fimbriated E. coli.

Bacterial infections of the urinary bladder are very common, and the role of mast cells in these infections is invariably thought of as a detrimental one. However, recent studies have shown that mast cells play a key role in host defense against various enterobacterial infections. In this manuscript, using mast cell-deficient (WBB6F1 - W/Wv) and mast cell-sufficient (WBB6F1 - +/+) mice we have investigated the protective role of mast cells in urinary bladder infections in vivo. Our findings show that (i) the mast cells are activated by FimH-expressing E. coli, and release large amount of histamine in the urinary bladder; (ii) the number of surviving bacteria in the urine is dependent on the presence of mast cells, and (iii) mast cell number in the bladder increases following uropathogenic infection in mice which is likely due to an increase in the mast cell growth-promoting cytokine IL-3 in bacteria-activated mast cells. Taken together, these observations suggest a beneficial role of mast cells in urinary bladder infections in mice.

Authors
Malaviya, R; Ikeda, T; Abraham, SN; Malaviya, R
MLA Citation
Malaviya, R, Ikeda, T, Abraham, SN, and Malaviya, R. "Contribution of mast cells to bacterial clearance and their proliferation during experimental cystitis induced by type 1 fimbriated E. coli." Immunol Lett 91.2-3 (February 15, 2004): 103-111.
PMID
15019277
Source
pubmed
Published In
Immunology Letters
Volume
91
Issue
2-3
Publish Date
2004
Start Page
103
End Page
111
DOI
10.1016/j.imlet.2003.10.005

Differential mast cell response to different bacteria

Mast cells (MCs) are highly specialized for the synthesis and secretion of pharmacologically active products. Although implicated in various inflammatory diseases such as asthma, allergy, multiple sclerosis, and Crohn's disease, MCs have also an important physiologic role in immunosurveillance and modulation of host's innate immune responses following bacterial infection. Here, we present that MCs show varying capability of recognizing and responding to different bacteria. Whereas MCs were readily degranulated and released neutrophil chemoattractants in response to E. coli or S. aureus infections, they failed to degranulate during S. typhimurium infections. Consequently, E. coli infections were associated with a vigorous neutrophil response and early bacterial clearance whereas S. typhimurium infections were associated limited neutrophil influx and bacterial multiplication at sites of infection. Interestingly, injection of compound 48/80, a MC specific activator, at sites of S. typhimurium infection triggered MC mediated neutrophil influx and bacterial clearance.

Authors
Kim, J; Abraham, SN
MLA Citation
Kim, J, and Abraham, SN. "Differential mast cell response to different bacteria." Journal of Bacteriology and Virology 34.4 (2004): 311-319.
Source
scival
Published In
Journal of Bacteriology and Virology
Volume
34
Issue
4
Publish Date
2004
Start Page
311
End Page
319

Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection.

Palpable swelling of regional lymph nodes is a common sequela of microbial infections but the mechanism responsible for the sequestration and subsequent coordination of lymphocyte responses within these dynamic structures remains poorly understood. Here we show that draining lymph nodes of mast cell-deficient mice did not demonstrate swelling after intradermal bacterial challenge. Testing of individual mast cell-derived products in this model indicated that tumor necrosis factor was the main mediator of nodal hypertrophy, whereas tryptase and histamine had no effect. After peripheral mast cell activation, both tumor necrosis factor concentrations and the recruitment of circulating T cells were increased within draining nodes. These results show a critical function for peripheral mast cell-derived tumor necrosis factor in regulating the hypertrophy of draining lymph nodes during infection.

Authors
McLachlan, JB; Hart, JP; Pizzo, SV; Shelburne, CP; Staats, HF; Gunn, MD; Abraham, SN
MLA Citation
McLachlan, JB, Hart, JP, Pizzo, SV, Shelburne, CP, Staats, HF, Gunn, MD, and Abraham, SN. "Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection." Nat Immunol 4.12 (December 2003): 1199-1205.
PMID
14595438
Source
pubmed
Published In
Nature Immunology
Volume
4
Issue
12
Publish Date
2003
Start Page
1199
End Page
1205
DOI
10.1038/ni1005

Mast cell activation by Mycobacterium tuberculosis: mediator release and role of CD48.

Mast cells (MC) are abundant in the lung and other peripheral tissue, where they participate in inflammatory processes against bacterial infections. Like other effector cells of the innate immune system, MC interact directly with a wide variety of infectious agents. This interaction results in MC activation and inflammatory mediator release. We demonstrated that MC interact with Mycobacterium tuberculosis, triggering the release of several prestored reagents, such as histamine and beta-hexosaminidase, and de novo synthesized cytokines, such as TNF-alpha and IL-6. A number of M. tuberculosis Ags, ESAT-6, MTSA-10, and MPT-63, have been implicated in MC activation and mediator release. A MC plasmalemmal protein, CD48, was implicated in interactions with mycobacteria because CD48 appeared to aggregate in the MC membrane at sites of bacterial binding and because Abs to CD48 inhibited the MC histamine response to mycobacteria. Cumulatively, these findings suggest that MC, even in the absence of opsonins, can directly recognize M. tuberculosis and its Ags and have the potential to play an active role in mediating the host's innate response to M. tuberculosis infection.

Authors
Muñoz, S; Hernández-Pando, R; Abraham, SN; Enciso, JA
MLA Citation
Muñoz, S, Hernández-Pando, R, Abraham, SN, and Enciso, JA. "Mast cell activation by Mycobacterium tuberculosis: mediator release and role of CD48." J Immunol 170.11 (June 1, 2003): 5590-5596.
PMID
12759438
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
170
Issue
11
Publish Date
2003
Start Page
5590
End Page
5596

Microbial entry through caveolae: variations on a theme.

Caveolae and lipid rafts are increasingly being recognized as a significant portal of entry into host cells for a wide variety of pathogenic microorganisms. Entry through this mechanism appears to afford the microbes protection from degradation in lysosomes, though the level to which each microbe actively participates in avoiding lysosomal fusion may vary. Other possible variations in microbial entry through caveolae or lipid rafts may include (i) the destination of trafficking after entry and (ii) how actively the microbe contributes to the caveolae lipid/raft mediated entry. It seems that, though a wide variety of microorganisms are capable of utilizing caveolae/lipid rafts in various stages of their intracellular lifestyle, there can be distinct differences in how each microbe interacts with these structures. By studying these variations, we may learn more about the normal functioning of these cellular microdomains, and perhaps of more immediate importance, how to incorporate the use of these structures into the treatment of both infectious and non-infectious disease.

Authors
Duncan, MJ; Shin, J-S; Abraham, SN
MLA Citation
Duncan, MJ, Shin, J-S, and Abraham, SN. "Microbial entry through caveolae: variations on a theme." Cell Microbiol 4.12 (December 2002): 783-791. (Review)
PMID
12464009
Source
pubmed
Published In
Cellular Microbiology
Volume
4
Issue
12
Publish Date
2002
Start Page
783
End Page
791

The role of mast cells in host defense and their subversion by bacterial pathogens.

Mast cells (MCs) play a prominent role in the early immune response to invading pathogenic bacteria. This newly discovered role for MCs involves the release of chemoattractants that recruit neutrophils and the direct phagocytosis and killing of opsonized bacteria. Whereas these activities are clearly beneficial to the host, certain pathogens have evolved mechanisms to evoke anomalous MC responses to the detriment of the host. These include evoking phagocytosis without killing of unopsonized bacteria and the production of toxins that corrupt the release of mediators by MCs. Elucidating how pathogens subvert the activities of MCs could provide clues to limiting the pathological activities of these cells during infectious diseases.

Authors
Féger, F; Varadaradjalou, S; Gao, Z; Abraham, SN; Arock, M
MLA Citation
Féger, F, Varadaradjalou, S, Gao, Z, Abraham, SN, and Arock, M. "The role of mast cells in host defense and their subversion by bacterial pathogens." Trends Immunol 23.3 (March 2002): 151-158. (Review)
PMID
11864844
Source
pubmed
Published In
Trends in Immunology
Volume
23
Issue
3
Publish Date
2002
Start Page
151
End Page
158

Symptomatic congenital syphilis presenting at birth.

We report here a case of congenital syphilis presenting in a newborn infant at birth. A negative infant VDRL test, pseudoparesis and more notably, joint swellings (arthritis) were features seen uncommonly. Florid skeletal involvement, which is rarely seen in the early neonatal period, prompted us to draw attention to the varied presentation of this disease, rightly referred to as the "master masquerader".

Authors
Narain, S; Batra, B; Abraham, SN; Arya, LS
MLA Citation
Narain, S, Batra, B, Abraham, SN, and Arya, LS. "Symptomatic congenital syphilis presenting at birth." Indian J Pediatr 68.9 (September 2001): 897-899.
PMID
11669044
Source
pubmed
Published In
The Indian Journal of Pediatrics
Volume
68
Issue
9
Publish Date
2001
Start Page
897
End Page
899

Cell biology. Caveolae--not just craters in the cellular landscape.

Authors
Shin, JS; Abraham, SN
MLA Citation
Shin, JS, and Abraham, SN. "Cell biology. Caveolae--not just craters in the cellular landscape." Science 293.5534 (August 24, 2001): 1447-1448.
PMID
11520975
Source
pubmed
Published In
Science
Volume
293
Issue
5534
Publish Date
2001
Start Page
1447
End Page
1448
DOI
10.1126/science.1061079

Caveolae as portals of entry for microbes.

Many pathogens, including many traditionally extracellular microbes, now appear capable of entry into host cells with limited loss of viability. A portal of entry shared by some bacteria, bacterial toxins, viruses and parasites are caveolae (or lipid rafts), which are involved in the import and intracellular translocation of macromolecules in host cells. A requirement for caveolae-mediated endocytosis of microbes appears to be that the respective receptor is a constituent of caveolae or must move to caveolae following ligation.

Authors
Shin, JS; Abraham, SN
MLA Citation
Shin, JS, and Abraham, SN. "Caveolae as portals of entry for microbes." Microbes Infect 3.9 (July 2001): 755-761. (Review)
PMID
11489424
Source
pubmed
Published In
Microbes and Infection
Volume
3
Issue
9
Publish Date
2001
Start Page
755
End Page
761

Studies of the multifaceted mast cell response to bacteria.

The concept of mast cells as playing a critical and multifaceted role in immune defense against pathogens is new, and effective ways to study and validate this notion are required. Recently, a number of approaches have been described that can be used to study the molecular aspects of mast cell recognition of pathogens, and of specific mast cell responses, such as mediator release, bacterial endocytosis and mast cell migration, to pathogens.

Authors
McLachlan, JB; Abraham, SN
MLA Citation
McLachlan, JB, and Abraham, SN. "Studies of the multifaceted mast cell response to bacteria." Curr Opin Microbiol 4.3 (June 2001): 260-266. (Review)
PMID
11378476
Source
pubmed
Published In
Current Opinion in Microbiology
Volume
4
Issue
3
Publish Date
2001
Start Page
260
End Page
266

Glycosylphosphatidylinositol-anchored receptor-mediated bacterial endocytosis.

An increasing number of pathogens or their toxins appear to utilize glycosylphosphatidylinositol(GPI)-anchored receptors to trigger entry into immune and other host cells. Since these receptors have no transmembrane and intracellular moieties, how endocytosis is initiated is unclear. Recently, CD48 on mast cell membranes was shown to trigger endocytosis of bacteria via a route that avoids fusion with lysosomes and by a mechanism involving discrete cellular entities called caveolae. The localization of CD48 within caveolae appears to be a prerequisite for caveolae-mediated bacterial entry.

Authors
Shin, JS; Abraham, SN
MLA Citation
Shin, JS, and Abraham, SN. "Glycosylphosphatidylinositol-anchored receptor-mediated bacterial endocytosis." FEMS Microbiol Lett 197.2 (April 13, 2001): 131-138. (Review)
PMID
11313125
Source
pubmed
Published In
Fems Microbiology Letters
Volume
197
Issue
2
Publish Date
2001
Start Page
131
End Page
138

Interaction of Bordetella pertussis with mast cells, modulation of cytokine secretion by pertussis toxin.

Together with macrophages and dendritic cells, mast cells have recently been shown to interact with certain pathogenic bacteria and present microbial antigens to the immune system. We show here that Bordetella pertussis can adhere to and be phagocytosed by mast cells. In addition, mast cells are able to process and present B. pertussis antigens to T lymphocytes. Furthermore, exposure of mast cells to B. pertussis induced the release of the proinflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). The release of IL-6 was strongly reduced by pertussis toxin expressed by B. pertussis. The production of IL-10, but not that of IL-4, by mast cells was also inhibited by pertussis toxin. Depletion of mast cells in vivo resulted in significant reduction of early TNF-alpha production in bronchoalveolar lavage (BAL) fluids of B. pertussis-infected mice. These data suggest that mast cells may play a role in the induction of immune responses against B. pertussis through the release of cytokines, especially TNF-alpha.

Authors
Mielcarek, N; Hörnquist, EH; Johansson, BR; Locht, C; Abraham, SN; Holmgren, J
MLA Citation
Mielcarek, N, Hörnquist, EH, Johansson, BR, Locht, C, Abraham, SN, and Holmgren, J. "Interaction of Bordetella pertussis with mast cells, modulation of cytokine secretion by pertussis toxin." Cell Microbiol 3.3 (March 2001): 181-188.
PMID
11260141
Source
pubmed
Published In
Cellular Microbiology
Volume
3
Issue
3
Publish Date
2001
Start Page
181
End Page
188

Mast cell modulation of immune responses to bacteria.

Mast cells are key elements of the immune system. These cells release a wide variety of pro-inflammatory mediators which are responsible for the pathophysiology of many allergic diseases. Recent studies, however, have shown that mast cells have the capacity to modulate the host's innate immune response to gram negative bacteria by their ability to phagocytose bacteria, process and present bacterial antigens to T cells and recruit phagocytic help through the release of physiological amounts of pro-inflammatory mediators. Here, current knowledge of mast cell responses to gram negative bacteria and molecular mechanisms associated with mast cell bacteria interaction is reviewed.

Authors
Malaviya, R; Abraham, SN
MLA Citation
Malaviya, R, and Abraham, SN. "Mast cell modulation of immune responses to bacteria." Immunol Rev 179 (February 2001): 16-24. (Review)
PMID
11292019
Source
pubmed
Published In
Immunological Reviews
Volume
179
Publish Date
2001
Start Page
16
End Page
24

Co-option of endocytic functions of cellular caveolae by pathogens.

It is increasingly becoming clear that various immune cells are infected by the very pathogens that they are supposed to attack. Although many mechanisms for microbial entry exist, it appears that a common route of entry shared by certain bacteria, viruses and parasites involves cellular lipid-rich microdomains sometimes called caveolae. These cellular entities, which are characterized by their preferential accumulation of glycosylphosphatidylinositol (GPI)-anchored molecules, cholesterol and various glycolipids, and a distinct protein (caveolin), are present in many effector cells of the immune system including neutrophils, macrophages, mast cells and dendritic cells. These structures have an innate capacity to endocytoze various ligands and traffic them to different intracellular sites and sometimes, back to the extracellular cell surface. Because caveolae do not typically fuse with lysosomes, the ligands borne by caveolar vesicles are essentially intact, which is in marked contrast to ligands endocytozed via the classical endosome-lysosome pathway. A number of microbes or their exotoxins co-opt the unique features of caveolae to enter and traffic, without any apparent loss of viability and function, to different sites within immune and other host cells. In spite of their wide disparity in size and other structural attributes, we predict that a common feature among caveolae-utilizing pathogens and toxins is that their cognate receptor(s) are localized within plasmalemmal caveolae of the host cell.

Authors
Shin, JS; Abraham, SN
MLA Citation
Shin, JS, and Abraham, SN. "Co-option of endocytic functions of cellular caveolae by pathogens." Immunology 102.1 (January 2001): 2-7. (Review)
PMID
11168630
Source
pubmed
Published In
Immunology
Volume
102
Issue
1
Publish Date
2001
Start Page
2
End Page
7

Type 1 fimbriated Escherichia coli-mast cell interactions in cystitis

Authors
Abraham, SN; Shin, J-S; Malaviya, R
MLA Citation
Abraham, SN, Shin, J-S, and Malaviya, R. "Type 1 fimbriated Escherichia coli-mast cell interactions in cystitis." Journal of Infectious Diseases 183.SUPPL. 1 (2001): S51-S55.
PMID
11171015
Source
scival
Published In
Journal of Infectious Diseases
Volume
183
Issue
SUPPL. 1
Publish Date
2001
Start Page
S51
End Page
S55
DOI
10.1086/318853

Involvement of cellular caveolae in bacterial entry into mast cells.

Caveolae are subcellular structures implicated in the import and transcytosis of macromolecules and in transmembrane signaling. To date, evidence for the existence of caveolae in hematopoietic cells has been ambiguous. Caveolae were detected in the microvilli and intracellular vesicles of cultured mouse bone marrow-derived mast cells (BMMCs). CD48, a receptor for FimH-expressing (type 1 fimbriated) Escherichia coli, was specifically localized to plasmalemmal caveolae in BMMCs. The involvement of caveolae in bacterial entry into BMMCs was indicated because caveolae-disrupting and -usurping agents specifically blocked E. coli entry, and markers of caveolae were actively recruited to sites of bacterial entry. The formation of bacteria-encapsulating caveolar chambers in BMMCs represents a distinct mechanism of microbial entry into phagocytes.

Authors
Shin, JS; Gao, Z; Abraham, SN
MLA Citation
Shin, JS, Gao, Z, and Abraham, SN. "Involvement of cellular caveolae in bacterial entry into mast cells." Science 289.5480 (August 4, 2000): 785-788.
PMID
10926542
Source
pubmed
Published In
Science
Volume
289
Issue
5480
Publish Date
2000
Start Page
785
End Page
788

Role of mast cell leukotrienes in neutrophil recruitment and bacterial clearance in infectious peritonitis.

Stimulated mast cells release a variety of chemotactic factors such as tumor necrosis factor alpha (TNF-alpha) and leukotriene B4. Recent studies have shown that mast cell-derived TNF-alpha plays a critical role in host defense against Gram negative bacterial infections by the recruitment of neutrophils to the sites of infection. In the present study, we sought to investigate if mast cells release leukotriene (LT) B4 in response to bacteria and, if so, to establish its in vivo relevance. We show that mast cells release significant amounts of LTB4 and LTC4 in response to exposure to FimH-expressing type 1 fimbriated Escherichia coli in vitro. To test the functional significance of mast cell-derived LTs during an E. coli infection in vivo, we examined the effect of a LT-synthesis inhibitor, A-63162, on bacterial clearance and neutrophil influx in an infectious peritonitis model in mast cell-deficient mice (WBB6F1-W/WV) and their normal congenic control (WBB6F1-+/+) mice. Our results show that a treatment with A-63162 reduced neutrophil influx and bacterial clearance in the peritoneal cavities of mast cell-sufficient but not -deficient mice. Thus, mast cell-derived LTs contribute to host defense by mediating early neutrophil influx and bacterial clearance at sites of infection.

Authors
Malaviya, R; Abraham, SN
MLA Citation
Malaviya, R, and Abraham, SN. "Role of mast cell leukotrienes in neutrophil recruitment and bacterial clearance in infectious peritonitis." J Leukoc Biol 67.6 (June 2000): 841-846.
PMID
10857857
Source
pubmed
Published In
Journal of leukocyte biology
Volume
67
Issue
6
Publish Date
2000
Start Page
841
End Page
846

Molecular mechanisms for the diversification of bacterial surface lectins.

Authors
Sharon, N; Hasty, D; Abraham, SN
MLA Citation
Sharon, N, Hasty, D, and Abraham, SN. "Molecular mechanisms for the diversification of bacterial surface lectins." ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 219 (March 26, 2000): U240-U240.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
219
Publish Date
2000
Start Page
U240
End Page
U240

Mast cell modulation of the innate immune response to enterobacterial infection.

Authors
Abraham, SN; Malaviya, R
MLA Citation
Abraham, SN, and Malaviya, R. "Mast cell modulation of the innate immune response to enterobacterial infection." Adv Exp Med Biol 479 (2000): 91-105. (Review)
PMID
10897412
Source
pubmed
Published In
Advances in experimental medicine and biology
Volume
479
Publish Date
2000
Start Page
91
End Page
105
DOI
10.1007/0-306-46831-X_8

Role of bacterial lectins in urinary tract infections. Molecular mechanisms for diversification of bacterial surface lectins.

Authors
Ofek, I; Hasty, DL; Abraham, SN; Sharon, N
MLA Citation
Ofek, I, Hasty, DL, Abraham, SN, and Sharon, N. "Role of bacterial lectins in urinary tract infections. Molecular mechanisms for diversification of bacterial surface lectins." Adv Exp Med Biol 485 (2000): 183-192. (Review)
PMID
11109105
Source
pubmed
Published In
Advances in experimental medicine and biology
Volume
485
Publish Date
2000
Start Page
183
End Page
192
DOI
10.1007/0-306-46840-9_25

Normal neutrophil function in cathepsin G-deficient mice.

Cathepsin G is a neutral serine protease that is highly expressed at the promyelocyte stage of myeloid development. We have developed a homologous recombination strategy to create a loss-of-function mutation for murine cathepsin G. Bone marrow derived from mice homozygous for this mutation had no detectable cathepsin G protein or activity, indicating that no other protease in bone marrow cells has the same specificity. Hematopoiesis in cathepsin G-/- mice is normal, and the mice have no overt abnormalities in blood clotting. Neutrophils derived from cathepsin G-/- mice have normal morphology and azurophil granule composition; these neutrophils also display normal phagocytosis and superoxide production and have normal chemotactic responses to C5a, fMLP, and interleukin-8. Although cathepsin G has previously shown to have broad spectrum antibiotic properties, challenges of mice with Staphylococcus aureus, Klebsiella pneumoniae, or Escherichia coli yielded survivals that were not different from those of wild-type animals. In sum, cathepsin G-/- neutrophils have no obvious defects in function; either cathepsin G is not required for any of these normal neutrophil functions or related azurophil granule proteases with different specificities (ie, neutrophil elastase, proteinase 3, azurocidin, and/or others) can substitute for it in vivo.

Authors
MacIvor, DM; Shapiro, SD; Pham, CT; Belaaouaj, A; Abraham, SN; Ley, TJ
MLA Citation
MacIvor, DM, Shapiro, SD, Pham, CT, Belaaouaj, A, Abraham, SN, and Ley, TJ. "Normal neutrophil function in cathepsin G-deficient mice." Blood 94.12 (December 15, 1999): 4282-4293.
PMID
10590073
Source
pubmed
Published In
Blood
Volume
94
Issue
12
Publish Date
1999
Start Page
4282
End Page
4293

Internalization of FimH+ Escherichia coli by the human mast cell line (HMC-1 5C6) involves protein kinase C.

Rodent mast cells (MC) play critical roles in host defense against bacterial infection. However, bacteria-mediated signaling mechanisms in MC have not been studied. In addition, the response of human MC to bacteria is not fully investigated. This study examined the interaction between human MC and type 1 fimbriated Escherichia coli and the mechanisms involved using the human MC line HMC-1 5C6 and human cord blood-derived MC. These MC internalized significant numbers of FimH+ E. coli, but not its isogenic FimH- mutant. In HMC-1 cells, bacterial internalization was stimulated by protein kinase C (PKC) activation [short-term phorbol myristate acetate (PMA) treatment] and dramatically decreased by PKC inhibitors or PKC depletion (long-term PMA treatment). Moreover, bacterial internalization was accompanied by significant expression of PKCbeta1 and delta. Fluorescence microscopy demonstrated accumulation of PKCbeta1 on internalized bacteria. These data indicate that human MC has the capacity to internalize bacteria and PKC may be a critical intracellular mediator of this function.

Authors
Lin, TJ; Gao, Z; Arock, M; Abraham, SN
MLA Citation
Lin, TJ, Gao, Z, Arock, M, and Abraham, SN. "Internalization of FimH+ Escherichia coli by the human mast cell line (HMC-1 5C6) involves protein kinase C." J Leukoc Biol 66.6 (December 1999): 1031-1038.
PMID
10614787
Source
pubmed
Published In
Journal of leukocyte biology
Volume
66
Issue
6
Publish Date
1999
Start Page
1031
End Page
1038

Inability of encapsulated Klebsiella pneumoniae to assemble functional type 1 fimbriae on their surface.

We screened phase variants of Klebsiella pneumoniae isolates for the expression of capsule and type 1 fimbriae and found that all of the 22 blood isolates were encapsulated and did not express type 1 fimbriae while 10 of 11 urinary tract isolates expressed type 1 fimbriae but were unencapsulated. Phase variants from selected isolates were found to be either unencapsulated and fimbriated or lacked both structures. Variants expressing both structures were not detected. Fimbrial subunits FimH and FimA were localized in the periplasmic space of the parent strain and on the surface of the unencapsulated variants. The results suggest that capsule formation impedes assembly of pre-formed fimbrial subunits on the bacterial surface.

Authors
Matatov, R; Goldhar, J; Skutelsky, E; Sechter, I; Perry, R; Podschun, R; Sahly, H; Thankavel, K; Abraham, SN; Ofek, I
MLA Citation
Matatov, R, Goldhar, J, Skutelsky, E, Sechter, I, Perry, R, Podschun, R, Sahly, H, Thankavel, K, Abraham, SN, and Ofek, I. "Inability of encapsulated Klebsiella pneumoniae to assemble functional type 1 fimbriae on their surface." FEMS Microbiol Lett 179.1 (October 1, 1999): 123-130.
PMID
10481096
Source
pubmed
Published In
Fems Microbiology Letters
Volume
179
Issue
1
Publish Date
1999
Start Page
123
End Page
130

Bacteria-host cell interaction mediated by cellular cholesterol/glycolipid-enriched microdomains.

Gram negative bacterial infection is a leading cause of fatality and is attributed, at least in part, to the bacteria's capacity to persist in the host in spite of appropriate antibiotic therapy. It has been suggested that bacteria evade antibiotics by hiding within host cells. We sought to investigate this important aspect of infections in mast cells, which are inflammatory cells found in close proximity to the host-environment interface and which have recently been reported to play a crucial role in the early innate immune response to bacteria. We examined mast cell interactions with FimH-expressing E. coli, one of the major opportunistic pathogens of humans. We determined that in serum free conditions, these bacteria were able to trigger mast cell uptake without loss of bacterial viability. CD48, a mannose containing GPI (glycosylphosphatidylinositol)-linked molecule was found to be the receptor of FimH-expressing E. coli in mouse mast cells. We found that the internalization via CD48 was blocked by filipin, a cholesterol binding drug known to disrupt cholesterol/glycolipid-enriched microdomains and the bacteria-encasing vacuoles were rich in cholesterol inside cells. Interestingly, we found that mast cells subsequently expelled majority of the intracellular bacteria in 24 hours. This expulsion process was blocked by lovastatin/cyclodextrin treatment, which is known to inhibit cellular trafficking of cholesterol/glycolipid-enriched microdomains. Thus, the bacterial entry into and expulsion from mast cells were critically dependent on cholesterol/glycolipid-enriched microdomains, which represents a novel mode of tussle between the pathogen and the mast cell occurring in opsonin deficient sites in the body or even at other sites in naive or immunocompromised hosts which have low systemic levels of E. coli specific antibody.

Authors
Shin, JS; Gao, Z; Abraham, SN
MLA Citation
Shin, JS, Gao, Z, and Abraham, SN. "Bacteria-host cell interaction mediated by cellular cholesterol/glycolipid-enriched microdomains." Biosci Rep 19.5 (October 1999): 421-432.
PMID
10763810
Source
pubmed
Published In
Bioscience Reports
Volume
19
Issue
5
Publish Date
1999
Start Page
421
End Page
432

The mast cell tumor necrosis factor alpha response to FimH-expressing Escherichia coli is mediated by the glycosylphosphatidylinositol-anchored molecule CD48.

Mast cells are well known for their harmful role in IgE-mediated hypersensitivity reactions, but their physiological role remains a mystery. Several recent studies have reported that mast cells play a critical role in innate immunity in mice by releasing tumor necrosis factor alpha (TNF-alpha) to recruit neutrophils to sites of enterobacterial infection. In some cases, the mast cell TNF-alpha response was triggered when these cells directly bound FimH on the surface of Escherichia coli. We have identified CD48, a glycosylphosphatidylinositol-anchored molecule, to be the complementary FimH-binding moiety in rodent mast cell membrane fractions. We showed that (i) pretreatment of mast cell membranes with antibodies to CD48 or phospholipase C inhibited binding of FimH+ E. coli, (ii) FimH+ E. coli but not a FimH- derivative bound isolated CD48 in a mannose-inhibitable manner, (iii) binding of FimH+ bacteria to Chinese hamster ovary (CHO) cells was markedly increased when these cells were transfected with CD48 cDNA, and (iv) antibodies to CD48 specifically blocked the mast cell TNF-alpha response to FimH+ E. coli. Thus, CD48 is a functionally relevant microbial receptor on mast cells that plays a role in triggering inflammation.

Authors
Malaviya, R; Gao, Z; Thankavel, K; van der Merwe, PA; Abraham, SN
MLA Citation
Malaviya, R, Gao, Z, Thankavel, K, van der Merwe, PA, and Abraham, SN. "The mast cell tumor necrosis factor alpha response to FimH-expressing Escherichia coli is mediated by the glycosylphosphatidylinositol-anchored molecule CD48." Proc Natl Acad Sci U S A 96.14 (July 6, 1999): 8110-8115.
PMID
10393956
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
96
Issue
14
Publish Date
1999
Start Page
8110
End Page
8115

Production of TNF-alpha by murine bone marrow derived mast cells activated by the bacterial fimbrial protein, FimH.

Production of tumor necrosis factor alpha (TNF-alpha) by mast cells is an important aspect of host defense against gram negative bacteria. In order to define the intracellular pathways utilized by mast cells in this physiological, protective role, we have studied the production of TNF-alpha in bone marrow derived mast cells from the C3H/HeJ (LPS-insensitive) strain following exposure to bacteria expressing the fimbrial protein, FimH. Mast cells exposed to FimH produce TNF-alpha (300-1200 pg/10(6) cells) over 1-3 h compared with 1800-15,000 pg/10(6) cells produced by cells triggered via IgE/antigen. This low level of TNF-alpha production in vitro is compatible with the protective in vivo role of mast cells to produce modest amounts of TNF-alpha in contrast to the large amounts of mediators released during maximal activation. A second difference between the two signals is sensitivity to cyclosporin A (CsA). The IgE/antigen pathway is inhibited by 90-95% at 0.02 to 0.5 microM cyclosporin A whereas the FimH pathway is inhibited by only 40%. These data demonstrate that the intracellular pathway activated by FimH is different from that activated by IgE/antigen both in terms of amount of TNF-alpha produced and in sensitivity to CsA. This is the first evidence that FimH activates mast cells via a pathway that is distinct from that used by IgE/antigen.

Authors
Dreskin, SC; Abraham, SN
MLA Citation
Dreskin, SC, and Abraham, SN. "Production of TNF-alpha by murine bone marrow derived mast cells activated by the bacterial fimbrial protein, FimH." Clin Immunol 90.3 (March 1999): 420-424.
PMID
10075872
Source
pubmed
Published In
Clinical Immunology
Volume
90
Issue
3
Publish Date
1999
Start Page
420
End Page
424
DOI
10.1006/clim.1998.4657

Molecular basis for the enterocyte tropism exhibited by Salmonella typhimurium type 1 fimbriae.

Salmonella typhimurium exhibits a distinct tropism for mouse enterocytes that is linked to their expression of type 1 fimbriae. The distinct binding traits of Salmonella type 1 fimbriae is also reflected in their binding to selected mannosylated proteins and in their ability to promote secondary bacterial aggregation on enterocyte surfaces. The determinant of binding in Salmonella type 1 fimbriae is a 35-kDa structurally distinct fimbrial subunit, FimHS, because inactivation of fimHS abolished binding activity in the resulting mutant without any apparent effect on fimbrial expression. Surprisingly, when expressed in the absence of other fimbrial components and as a translational fusion protein with MalE, FimHS failed to demonstrate any specific binding tropism and bound equally to all cells and mannosylated proteins tested. To determine if the binding specificity of Salmonella type 1 fimbriae was determined by the fimbrial shaft that is intimately associated with FimHS, we replaced the amino-terminal half of FimHS with the corresponding sequence from Escherichia coli FimH (FimHE) that contains the receptor binding domain of FimHE. The resulting hybrid fimbriae bearing FimHES on a Salmonella fimbrial shaft exhibited binding traits that resembled that of Salmonella rather than E. coli fimbriae. Apparently, the quaternary constraints imposed by the fimbrial shaft on the adhesin determine the distinct binding traits of S. typhimurium type 1 fimbriae.

Authors
Thankavel, K; Shah, AH; Cohen, MS; Ikeda, T; Lorenz, RG; Curtiss, R; Abraham, SN
MLA Citation
Thankavel, K, Shah, AH, Cohen, MS, Ikeda, T, Lorenz, RG, Curtiss, R, and Abraham, SN. "Molecular basis for the enterocyte tropism exhibited by Salmonella typhimurium type 1 fimbriae." J Biol Chem 274.9 (February 26, 1999): 5797-5809.
PMID
10026202
Source
pubmed
Published In
The Journal of biological chemistry
Volume
274
Issue
9
Publish Date
1999
Start Page
5797
End Page
5809

Transcytosis of FimH-expressing Gram negative bacteria in mast cells by coopting cholesterol-enriched microdomains.

Authors
Shin, JS; Gao, ZM; Baorto, D; Malaviya, R; Abraham, SN
MLA Citation
Shin, JS, Gao, ZM, Baorto, D, Malaviya, R, and Abraham, SN. "Transcytosis of FimH-expressing Gram negative bacteria in mast cells by coopting cholesterol-enriched microdomains." JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 103.1 (January 1999): S192-S193.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
103
Issue
1
Publish Date
1999
Start Page
S192
End Page
S193

Intracellular carriage of gram negative bacteria by mast cells and its possible contribution to septic shock.

Authors
Gao, ZM; Shin, JS; Malaviya, R; Abraham, SN
MLA Citation
Gao, ZM, Shin, JS, Malaviya, R, and Abraham, SN. "Intracellular carriage of gram negative bacteria by mast cells and its possible contribution to septic shock." JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 103.1 (January 1999): S42-S43.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
103
Issue
1
Publish Date
1999
Start Page
S42
End Page
S43

Bacterial up-take by human mast cells require protein kinase C.

Authors
Lin, TJ; Gao, Z; Arick, M; Abraham, SN
MLA Citation
Lin, TJ, Gao, Z, Arick, M, and Abraham, SN. "Bacterial up-take by human mast cells require protein kinase C." JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 103.1 (January 1999): S40-S40.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
103
Issue
1
Publish Date
1999
Start Page
S40
End Page
S40

Nonopsonic FIMH-Mediated phagocytosis of E. coli and its possible contribution to recurrent urinary tract infections

Authors
Abraham, SN; Baorto, DM
MLA Citation
Abraham, SN, and Baorto, DM. "Nonopsonic FIMH-Mediated phagocytosis of E. coli and its possible contribution to recurrent urinary tract infections." Advances in Cellular and Molecular Biology of Membranes and Organelles 6.C (1999): 333-348.
Source
scival
Published In
Advances in Cellular and Molecular Biology of Membranes and Organelles
Volume
6
Issue
C
Publish Date
1999
Start Page
333
End Page
348
DOI
10.1016/S1874-5172(99)80019-4

Phagocytic and tumor necrosis factor alpha response of human mast cells following exposure to gram-negative and gram-positive bacteria.

Recent studies have implicated rodent mast cells in the innate immune response to infectious bacteria. We report that cord blood-derived human mast cells (CBHMC) obtained from culture of cord blood progenitors phagocytozed and killed various gram-negative and gram-positive bacteria and simultaneously released considerable amounts of tumor necrosis factor alpha. Overall, the extent of the endocytic and exocytic response of CBHMC correlated with the number of adherent bacteria. Thus, human mast cells are intrinsically capable of mediating microbial recognition and of actively contributing to the host defense against bacteria.

Authors
Arock, M; Ross, E; Lai-Kuen, R; Averlant, G; Gao, Z; Abraham, SN
MLA Citation
Arock, M, Ross, E, Lai-Kuen, R, Averlant, G, Gao, Z, and Abraham, SN. "Phagocytic and tumor necrosis factor alpha response of human mast cells following exposure to gram-negative and gram-positive bacteria." Infect Immun 66.12 (December 1998): 6030-6034.
PMID
9826392
Source
pubmed
Published In
Infection and immunity
Volume
66
Issue
12
Publish Date
1998
Start Page
6030
End Page
6034

Mast cells and basophils in innate immunity.

Mast cells and basophils are primarily associated with the pathophysiology of allergic diseases. Considering that these cells have been preserved through evolution they must serve a valuable function. Intrinsically, mast cells are ideally placed and well endowed with inflammatory mediators to play a critical role in immune surveillance. Recent studies have shown that mast cells and basophils can bind various bacteria even in the absence of opsonizing antibodies. The resulting interaction caused release of a variety of inflammatory mediators and, in the case of mast cells, also uptake of bacteria. Among the mediators released by these inflammatory cells, TNF-alpha appears critical as it potentiates the early neutrophil responses to bacteria. Observations in mutant mice that are deficient in mast cells has provided further evidence for the specific role of mast cells in host defense against bacteria. We believe that there is now sufficient evidence (at least for mast cells) to propose a multi-faceted and significant role for these cells in the host's innate immune response to infectious agents.

Authors
Abraham, SN; Arock, M
MLA Citation
Abraham, SN, and Arock, M. "Mast cells and basophils in innate immunity." Semin Immunol 10.5 (October 1998): 373-381. (Review)
PMID
9799712
Source
pubmed
Published In
Seminars in Immunology
Volume
10
Issue
5
Publish Date
1998
Start Page
373
End Page
381
DOI
10.1006/smim.1998.0140

Clinical implications of mast cell-bacteria interaction.

Mast cells are traditionally known for mediating allergic reactions. In addition, these cells have been implicated in the pathogenesis of a variety of clinical conditions such as atopic and contact dermatitis, bullous pemphigoid, fibrotic lung disease, neurofibromatosis, psoriasis, scleroderma, rheumatoid arthritis, interstitial cystitis, ulcerative colitis, and Crohn's disease, but their role in host defense was an enigma until recently. Owing to the strategic location of mast cells at the host environment interface, their role in bacterial infections has been studied by a number of investigators. Latest reports show that mast cells have an ability to modulate the host's innate immune response to infectious agents. This review discusses the clinical implications of mast cell-bacteria interactions.

Authors
Malaviya, R; Abraham, SN
MLA Citation
Malaviya, R, and Abraham, SN. "Clinical implications of mast cell-bacteria interaction." J Mol Med (Berl) 76.9 (August 1998): 617-623. (Review)
PMID
9725764
Source
pubmed
Published In
Journal of Molecular Medicine
Volume
76
Issue
9
Publish Date
1998
Start Page
617
End Page
623

Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis.

Neutrophil elastase (NE) is a potent serine proteinase whose expression is limited to a narrow window during myeloid development. In neutrophils, NE is stored in azurophil granules along with other serine proteinases (cathepsin G, proteinase 3 and azurocidin) at concentrations exceeding 5 mM. As a result of its capacity to efficiently degrade extracellular matrix, NE has been implicated in a variety of destructive diseases. Indeed, while much interest has focused on the pathologic effects of this enzyme, little is known regarding its normal physiologic function(s). Because previous in vitro data have shown that NE exhibits antibacterial activity, we investigated the role of NE in host defense against bacteria. Generating strains of mice deficient in NE (NE-/-) by targeted mutagenesis, we show that NE-/- mice are more susceptible than their normal littermates to sepsis and death following intraperitoneal infection with Gram negative (Klebsiella pneumoniae and Escherichia coli) but not Gram positive (Staphylococcus aureus) bacteria. Our data indicate that neutrophils migrate normally to sites of infection in the absence of NE, but that NE is required for maximal intracellular killing of Gram negative bacteria by neutrophils.

Authors
Belaaouaj, A; McCarthy, R; Baumann, M; Gao, Z; Ley, TJ; Abraham, SN; Shapiro, SD
MLA Citation
Belaaouaj, A, McCarthy, R, Baumann, M, Gao, Z, Ley, TJ, Abraham, SN, and Shapiro, SD. "Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis." Nat Med 4.5 (May 1998): 615-618.
PMID
9585238
Source
pubmed
Published In
Nature Medicine
Volume
4
Issue
5
Publish Date
1998
Start Page
615
End Page
618

Fimbriae-mediated host-pathogen cross-talk.

Recent studies show that the coupling of fimbrial adhesins of uropathogenic Escherichia coli and pathogenic Neisseria species to their complementary receptors on host cells is a dynamic event, involving specific signaling to the bacteria as well as to the host cell. These studies have unveiled intriguing and novel mechanisms by which bacteria utilize their fimbriae to promote virulence at the mucosal surface and in deeper tissue.

Authors
Abraham, SN; Jonsson, AB; Normark, S
MLA Citation
Abraham, SN, Jonsson, AB, and Normark, S. "Fimbriae-mediated host-pathogen cross-talk." Curr Opin Microbiol 1.1 (February 1998): 75-81. (Review)
PMID
10066469
Source
pubmed
Published In
Current Opinion in Microbiology
Volume
1
Issue
1
Publish Date
1998
Start Page
75
End Page
81

Survival of FimH-expressing enterobacteria in macrophages relies on glycolipid traffic.

Strains of Escherichia coli persist within the human gut as normal commensals, but are frequent pathogens and can cause recurrent infection. Here we show that, in contrast to E. coli subjected to opsonic interactions stimulated by the host's immune response, E. coli that bind to the macrophage surface exclusively through the bacterial lectin FimH can survive inside the cell following phagocytosis. This viability is largely due to the attenuation of intracellular free-radical release and of phagosome acidification during FimH-mediated internalization, both of which are triggered by antibody-mediated internalization. This different processing of non-opsonized bacteria is supported by morphological evidence of tight-fitting phagosomes compared with looser, antibody-mediated phagosomes. We propose that non-opsonized FimH-expressing E. coli co-opt internalization of lipid-rich microdomains following binding to the FimH receptor, the glycosylphosphatidylinositol-linked protein CD48, because (1) the sterol-binding agents filipin, nystatin and methyl beta-cyclodextrin specifically block FimH-mediated internalization; (2) CD48 and the protein caveolin both accumulate on macrophage membranes surrounding bacteria; and (3) antibodies against CD48 inhibit FimH-mediated internalization. Our findings bring the traditionally extracellular E. coli into the realm of opportunistic intracellular parasitism and suggest how opportunistic infections with FimH-expressing enterobacteria could occur in a setting deprived of opsonizing antibodies.

Authors
Baorto, DM; Gao, Z; Malaviya, R; Dustin, ML; van der Merwe, A; Lublin, DM; Abraham, SN
MLA Citation
Baorto, DM, Gao, Z, Malaviya, R, Dustin, ML, van der Merwe, A, Lublin, DM, and Abraham, SN. "Survival of FimH-expressing enterobacteria in macrophages relies on glycolipid traffic." Nature 389.6651 (October 9, 1997): 636-639.
PMID
9335508
Source
pubmed
Published In
Nature
Volume
389
Issue
6651
Publish Date
1997
Start Page
636
End Page
639
DOI
10.1038/39376

Localization of a domain in the FimH adhesin of Escherichia coli type 1 fimbriae capable of receptor recognition and use of a domain-specific antibody to confer protection against experimental urinary tract infection.

The FimH subunit of type 1-fimbriated Escherichia coli has been implicated as an important determinant of bacterial adherence and colonization of the urinary tract. Here, we sought to localize the functionally important domain(s) within the FimH molecule and to determine if antibodies against this domain would block adherence of type 1-fimbriated E. coli to the bladder mucosa in situ and in vivo in an established mouse model of cystitis. We generated translational fusion proteins of disparate regions of the FimH molecule with an affinity tag MalE, and tested each of the fusion products in vitro for functional activity. The minimum region responsible for binding mouse bladder epithelial cells and a soluble mannoprotein, horseradish peroxidase, was contained within residues 1-100 of the FimH molecule. We validated and extended these findings by demonstrating that antibodies directed at the putative binding region of FimH or at synthetic peptides corresponding to epitopes within the binding domain could specifically block type 1 fimbriae-mediated bacterial adherence to bladder epithelial cells in situ and yeast cells in vitro. Next, we compared the ability of mice passively immunized intraperitoneally with antisera raised against residues 1-25 and 253-264 of FimH or 1-13 of FimA to resist bladder colonization in vivo after intravesicular challenge with type 1-fimbriated E. coli. Only the antibody directed at the putative binding region of FimH (anti- s-FimH1-25) significantly reduced E. coli bladder infections in the experimental mouse model of urinary tract infections. Similar results were obtained when the mice were actively immunized with synthetic peptides corresponding to residues 1-25 and 253-264 of FimH or 1-13 of FimA. The mechanism of protection was attributed, at least in part, to inhibition of bacterial adherence to the bladder surface by s-FimH1-25-specific antibody molecules that had filtered through the kidneys into the urine. The level of FimH antibodies entering the bladder from the circulatory system of the immunized mice was found to be markedly enhanced upon bacterial challenge. The potential broad spectrum activity of the protective FimH antibody was indicated from its serologic cross-reactivity with various urinary tract bacterial isolates bearing type 1 fimbriae. These findings could be relevant in the design of an efficacious and broadly reactive FimH vaccine against urinary tract infections.

Authors
Thankavel, K; Madison, B; Ikeda, T; Malaviya, R; Shah, AH; Arumugam, PM; Abraham, SN
MLA Citation
Thankavel, K, Madison, B, Ikeda, T, Malaviya, R, Shah, AH, Arumugam, PM, and Abraham, SN. "Localization of a domain in the FimH adhesin of Escherichia coli type 1 fimbriae capable of receptor recognition and use of a domain-specific antibody to confer protection against experimental urinary tract infection." J Clin Invest 100.5 (September 1, 1997): 1123-1136.
PMID
9276729
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
100
Issue
5
Publish Date
1997
Start Page
1123
End Page
1136
DOI
10.1172/JCI119623

Mast cells in infection and immunity.

Authors
Abraham, SN; Malaviya, R
MLA Citation
Abraham, SN, and Malaviya, R. "Mast cells in infection and immunity." Infect Immun 65.9 (September 1997): 3501-3508. (Review)
PMID
9284112
Source
pubmed
Published In
Infection and immunity
Volume
65
Issue
9
Publish Date
1997
Start Page
3501
End Page
3508

Mast cells as modulators of host defense in the lung.

Mast cells display a distinct spatial distribution in the lung where they are found preferentially in intraepithelial locations or in deeper tissue around blood vessels, bronchioles and mucus secreting glands. Yet the physiological role of these granule-laden cells is unknown. There are now intriguing signs that their distinctive distribution together with their intrinsic capacity to release large amounts of inflammatory mediators serve a critical role in immune surveillance. Mast cells have now been shown to be capable of recognizing and aggressively reacting to a wide range of bacteria. The mast cell responses involve ingesting and killing of adherent bacteria, in a manner not unlike that of traditional phagocytic cells. Concomitant with this endocytic activity, a large variety of potent inflammatory mediators are released by the mast cell. One such mast cell-derived mediator, TNF-alpha, was recently shown to be a critical signal for initiating neutrophil influx to sites of bacterial infection in the lung as well as the peritoneum of mice. This capacity of mast cells to recruit neutrophils, together with its recently reported participation in processing and presenting bacterial antigens to immune cells and in mediating proliferation of epithelial cells and mucosal mucus secretion, indicate that mast cells have an extraordinary ability to modulate the innate as well as adaptive immune responses to infectious microorganisms.

Authors
Abraham, SN; Thankavel, K; Malaviya, R
MLA Citation
Abraham, SN, Thankavel, K, and Malaviya, R. "Mast cells as modulators of host defense in the lung. (Published online)" Front Biosci 2 (February 15, 1997): d78-d87. (Review)
PMID
9159215
Source
pubmed
Published In
Frontiers in bioscience : a journal and virtual library
Volume
2
Publish Date
1997
Start Page
d78
End Page
d87

Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha

Authors
Malaviya, R; Ideda, R; Ross, E; Abraham, SN
MLA Citation
Malaviya, R, Ideda, R, Ross, E, and Abraham, SN. "Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha." Pneumologie 51.8 (1997): 869--.
Source
scival
Published In
Pneumologie
Volume
51
Issue
8
Publish Date
1997
Start Page
869-

Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha.

Although mast cells have been implicated in a variety of inflammatory conditions including immediate hypersensitivity and interstitial cystitis, their physiological role in the body is unknown. We investigated the role of mast cells in host defence against bacterial infections using a well characterized mast-cell-deficiency mouse model. We report here that mast cells, which are selectively located at portals of bacterial entry, are important to host defence. Mast-cell-deficient WBB6F1-W/Wv mice (W/Wv) were up to 20-fold less efficient in clearing enterobacteria than control WBB6F1 +/+ (+/+) mice or mast-cell-reconstituted W/Wv (W/Wv+MC) mice. With higher bacteria inocula, only W/Wv mice died (80%). The limited bacterial clearance in W/Wv mice directly correlated with impaired neutrophil influx. The mast-cell chemoattractant TNF-alpha was implicated in the neutrophil response because TNF-alpha was locally released only in +/+ and W/Wv+MC mice, TNF-alpha-specific antibodies blocked over 70% of the neutrophil influx, and purified mast cells released TNF-alpha upon incubation with bacteria. Additionally, the type-1 fimbrial subunit, FimH, was the necessary enterobacterial component for mast-cell activation and neutrophil influx because an isogenic FimH- mutant evoked a limited neutrophil response in +/+ mice compared to wild-type bacteria.

Authors
Malaviya, R; Ikeda, T; Ross, E; Abraham, SN
MLA Citation
Malaviya, R, Ikeda, T, Ross, E, and Abraham, SN. "Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha." Nature 381.6577 (May 2, 1996): 77-80.
PMID
8609993
Source
pubmed
Published In
Nature
Volume
381
Issue
6577
Publish Date
1996
Start Page
77
End Page
80
DOI
10.1038/381077a0

Mast cells process bacterial Ags through a phagocytic route for class I MHC presentation to T cells.

The pivotal role of mast cells in allergic reactions and inflammatory processes is well established and recent studies have suggested that mast cells may also have a role in specific immune responses. Because mast cells have been shown to phagocytose and kill enterobacteria, we wished to determine whether they could also process bacterial Ags for presentation to T cells. Using a model system in which a well-characterized T cell epitope is expressed within bacteria as a fusion protein, we demonstrate in this paper that mast cells are indeed capable of processing bacterial Ags for presentation through class I MHC molecules to T cell hybridomas after phagocytic uptake of live bacteria. Processing occurs from a number of Gram-negative enterobacteria including Salmonella typhimurium and Escherichia coli. Parallel assays show that processing of the model Ag from enterobacteria by mast cells is similar in efficiency to processing by peritoneal macrophages. Consistent with earlier observations demonstrating a function of the bacterial fimbrial protein FimH in promoting bacterial binding to mast cells, the magnitude of the Ag processing response of E. coli is influenced by bacterial expression of FimH. Taken together, these observations extend the range of cell types capable of the phagocytic pathway of Ag processing and suggest that mast cells may have a previously unrecognized role in the induction of specific immune responses to bacteria.

Authors
Malaviya, R; Twesten, NJ; Ross, EA; Abraham, SN; Pfeifer, JD
MLA Citation
Malaviya, R, Twesten, NJ, Ross, EA, Abraham, SN, and Pfeifer, JD. "Mast cells process bacterial Ags through a phagocytic route for class I MHC presentation to T cells." J Immunol 156.4 (February 15, 1996): 1490-1496.
PMID
8568252
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
156
Issue
4
Publish Date
1996
Start Page
1490
End Page
1496

Bacteria--Mast Cell Interactions in Inflammatory Disease.

Chronic inflammatory diseases of the gastrointestinal tract such as ulcerative colitis and Crohn's disease are characterized by mast cell proliferation and secretion of inflammatory mediators. The determinant(s) responsible for stimulating mast cells in the intestinal mucosa is not known. We investigated the interaction of mast cells with type 1 fimbriated Escherichia coli, an opportunistic pathogen and a constituent of the normal indigenous microflora of the gut. Unlike a mutant derivative deficient in the FimH subunit of the fimbriae or nonfimbriated E. coli, type 1 fimbriated E. coli adhered avidly to mast cells. As a consequence of this interaction, the mast cells phagocytozed and killed adherent bacteria. The mast cell bactericidal activity involved generation of superoxide anion and acidification of phagocytic vacuoles. In addition, many of the mast cells had degranulated and released inflammatory mediators such as histamine. These observations have implications both for normal host defense and for the initiation and perpetuation of inappropriate inflammatory responses in the gastrointestinal tract.

Authors
Malaviya, R; Ikeda, T; Ross, EA; Jakschik, BA; Abraham, SN
MLA Citation
Malaviya, R, Ikeda, T, Ross, EA, Jakschik, BA, and Abraham, SN. "Bacteria--Mast Cell Interactions in Inflammatory Disease." Am J Ther 2.10 (October 1995): 787-792.
PMID
11854788
Source
pubmed
Published In
American Journal of Therapeutics
Volume
2
Issue
10
Publish Date
1995
Start Page
787
End Page
792

FimH adhesin of type 1 pili is assembled into a fibrillar tip structure in the Enterobacteriaceae.

Type 1 pili are heteropolymeric mannosebinding fibers produced by all members of the Enterobacteriaceae family. The bulk of the fiber is composed of FimA. Two macromolecular complexes responsible for mediating an interaction with mannose-containing receptors were purified from fimA- Escherichia coli by mannose affinity chromatography and ion-exchange chromatography. One complex contained only the mannose-binding adhesin, FimH, associated with FimG, a minor component of the type 1 pilus. In the other complex the FimG-FimH moiety was loosely associated with a chaperone-minor subunit complex (FimC-FimF), possibly representing an intermediate in tip fibrilla assembly. The FimC chaperone has also been shown to form a preassembly complex with FimH that has been purified and characterized previously. Purified FimC did not bind to the FimG-FimH complex but did recognize FimH dissociated from the FimG-FimH complex. Quick-freeze deep-etch electron microscopy revealed that the FimG-FimH complex had a thin fibrillar architecture. High-resolution electron microscopy of type 1 pili revealed that a 16-nm fibrillar tip structure with an architecture identical to that of the FimG-FimH complex was joined end-to-end to the pilus rod. In a fimH- deletion mutant, the tip fibrillae joined to pilus rods were approximately 3 nm in length. The full-length tip fibrilla was restored by complementation with the fimH gene in trans. The bipartite nature of the type 1 pilus was also demonstrated on pili purified from clinical isolates of members of the Enterobacteriaceae family arguing that it is a conserved feature of the type 1 pilus.

Authors
Jones, CH; Pinkner, JS; Roth, R; Heuser, J; Nicholes, AV; Abraham, SN; Hultgren, SJ
MLA Citation
Jones, CH, Pinkner, JS, Roth, R, Heuser, J, Nicholes, AV, Abraham, SN, and Hultgren, SJ. "FimH adhesin of type 1 pili is assembled into a fibrillar tip structure in the Enterobacteriaceae." Proc Natl Acad Sci U S A 92.6 (March 14, 1995): 2081-2085.
PMID
7892228
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
92
Issue
6
Publish Date
1995
Start Page
2081
End Page
2085

Interaction of bacteria with mast cells.

Authors
Malaviya, R; Abraham, SN
MLA Citation
Malaviya, R, and Abraham, SN. "Interaction of bacteria with mast cells." Methods Enzymol 253 (1995): 27-43. (Review)
PMID
7476393
Source
pubmed
Published In
Methods in Enzymology
Volume
253
Publish Date
1995
Start Page
27
End Page
43

The PapG tip adhesin of P fimbriae protects Escherichia coli from neutrophil bactericidal activity.

Compared with Escherichia coli ORN103, a nonfimbriated K-12 strain, P-fimbriated E. coli ORN103/pPAP5 was found to interact poorly with human neutrophils and resist their bactericidal activity in vitro. PapG, the Gal alpha(1-->4)Gal binding moiety located at the distal end of the P fimbrial filament, appeared to be responsible for this effect because an isogenic PapG- mutant, E. coli ORN103/pPAP24, exhibited binding interactions with neutrophils that were similar to nonfimbriated E. coli ORN103. Although no direct evidence is available, the poor adherence mediated by PapG could be related to its electrostatic properties because the isolated PapG protein had a pI of 5.2, which indicated that in the physiological pH range it possessed a net negative charge. Antibodies against PapG overcame the protective effect of PapG and markedly enhanced the interactions of P-fimbriated E. coli with neutrophils resulting in bacterial killing. When a P-fimbriated clinical E. coli strain or its isogenic PapG- derivative was injected into the peritoneal cavities of mice, a similar number of neutrophils was recruited to the site of injection. After 2 h, the number of P-fimbriated E. coli organisms that survived the neutrophil influx in the mouse peritoneum was approximately four times more than the number of surviving PapG- bacteria. This result demonstrates that the PapG protein, which is strategically located at the distal region of the P-fibrillum structure, protects E. coli from the bactericidal action of neutrophils.

Authors
Tewari, R; Ikeda, T; Malaviya, R; MacGregor, JI; Little, JR; Hultgren, SJ; Abraham, SN
MLA Citation
Tewari, R, Ikeda, T, Malaviya, R, MacGregor, JI, Little, JR, Hultgren, SJ, and Abraham, SN. "The PapG tip adhesin of P fimbriae protects Escherichia coli from neutrophil bactericidal activity." Infect Immun 62.12 (December 1994): 5296-5304.
PMID
7960108
Source
pubmed
Published In
Infection and immunity
Volume
62
Issue
12
Publish Date
1994
Start Page
5296
End Page
5304

Mast cell degranulation induced by type 1 fimbriated Escherichia coli in mice.

The strategic location of mast cells at the host-environment interface and their ability to release potent mediators of inflammation have suggested that these cells may play a pivotal role in host defense against bacterial infection. The ability of the opportunistic pathogen, Escherichia coli, to induce degranulation of mast cells obtained from the mouse peritoneum was investigated. We determined that unlike a mutant derivative deficient in the FimH subunit of the fimbriae or nonfimbriated E. coli, type 1 fimbriated E. coli induced mast cell degranulation in vitro. The magnitude of mast cell degranulation was directly proportional to the number of adherent bacteria on the cell surface in the initial period of the interaction. Using a mouse model of bacterial peritonitis, we demonstrated mast cell degranulation and histamine release by type 1 fimbriated bacteria in vivo. Furthermore, beads coated with FimH but not with FimA, the major subunit of type 1 fimbriae, evoked mast cell release of histamine in vivo in amounts comparable to that elicited by type 1 fimbriated E. coli. These studies reveal that mast cells can be degranulated by interaction with type 1 fimbriated E. coli and that FimH, the mannose-binding component of the fimbriae, is a potent mast cell stimulant.

Authors
Malaviya, R; Ross, E; Jakschik, BA; Abraham, SN
MLA Citation
Malaviya, R, Ross, E, Jakschik, BA, and Abraham, SN. "Mast cell degranulation induced by type 1 fimbriated Escherichia coli in mice." J Clin Invest 93.4 (April 1994): 1645-1653.
PMID
7512987
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
93
Issue
4
Publish Date
1994
Start Page
1645
End Page
1653
DOI
10.1172/JCI117146

Type 1 fimbrial shafts of Escherichia coli and Klebsiella pneumoniae influence sugar-binding specificities of their FimH adhesins.

The type 1 fimbriae of enterobacteria comprise FimA, which constitutes most of the fimbrial shaft, and a cassette of three minor ancillary subunits including FimH, the mannose-binding moiety. The sugar-binding specificities of Escherichia coli and Klebsiella pneumoniae type 1 fimbriae were examined by determining the relative activities of two aromatic mannosides in inhibiting the yeast aggregation caused by the fimbriated bacteria. 4-Methylumbelliferyl alpha-mannoside (MeUmb alpha Man) was approximately 10-fold more effective than p-nitrophenyl alpha-mannoside (p-NP alpha Man) in inhibiting the yeast aggregation caused by the recombinant expressing native E. coli type 1 fimbriae. In contrast, MeUmb alpha Man was only fourfold more effective than p-NP alpha Man in assays employing the recombinant expressing native K. pneumoniae type 1 fimbriae. In order to elucidate the molecular mechanisms underlying the sugar-binding specificities of type 1 fimbriae in the two species, transcomplementation studies were performed and resulted in the creation of recombinants expressing two types of hybrid fimbriae: one consisting of a cassette of minor subunits of E. coli fimbriae borne on a filamentous shaft of K. pneumoniae FimA subunits and the other consisting of a cassette of K. pneumoniae minor fimbrial subunits borne on a shaft of E. coli FimA subunits. Although the heterologous FimH was incorporated into the fimbrial filaments in amounts comparable to those observed in native fimbriae, the hemagglutination activities of recombinants expressing hybrid fimbriae were significantly lower than those of their counterparts bearing native fimbriae. The sugar-binding specificity of the recombinant expressing hybrid fimbriae consisting of an E. coli shaft bearing K. pneumoniae FimH was different from those of recombinants expressing native K. pneumoniae fimbriae in its affinity for the two aromatic sugars but was remarkably similar to the specificities exhibited by recombinants expressing native E. coli fimbriae. Conversely, the sugar-binding specificity of the recombinant expressing hybrid fimbriae consisting of a K. pneumoniae shaft bearing E. coli FimH was different from that of the recombinant expressing native E. coli fimbriae but was very similar to those of recombinants expressing native K. pneumoniae fimbriae. We conclude that the differences in the sugar-binding specificity between E. coli and K. pneumoniae FimH fimbrial subunits is influenced by the fimbrial shafts which carry the adhesin molecules in a functionally competent form at the distal tips.

Authors
Madison, B; Ofek, I; Clegg, S; Abraham, SN
MLA Citation
Madison, B, Ofek, I, Clegg, S, and Abraham, SN. "Type 1 fimbrial shafts of Escherichia coli and Klebsiella pneumoniae influence sugar-binding specificities of their FimH adhesins." Infect Immun 62.3 (March 1994): 843-848.
PMID
7906676
Source
pubmed
Published In
Infection and immunity
Volume
62
Issue
3
Publish Date
1994
Start Page
843
End Page
848

Mast cell phagocytosis of FimH-expressing enterobacteria.

Most studies of mast cells have been directed at their role in the pathophysiology of IgE-mediated allergic reactions with little recognition of their participation in bacterial infections. We report that mast cells can specifically bind FimH, a mannose-binding subunit on type 1 fimbriae expressed by Escherichia coli and other enterobacteria. This interaction triggers mast cell phagocytosis and killing of the bacteria within vacuoles and through the release of superoxide anions. Also, in view of the fact that mast cells have the capacity to release inflammatory mediators and are particularly abundant in the skin, mucosal surfaces, and around blood vessels, we suggest that these cells play an important role in host defense against microbial infection.

Authors
Malaviya, R; Ross, EA; MacGregor, JI; Ikeda, T; Little, JR; Jakschik, BA; Abraham, SN
MLA Citation
Malaviya, R, Ross, EA, MacGregor, JI, Ikeda, T, Little, JR, Jakschik, BA, and Abraham, SN. "Mast cell phagocytosis of FimH-expressing enterobacteria." J Immunol 152.4 (February 15, 1994): 1907-1914.
PMID
8120397
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
152
Issue
4
Publish Date
1994
Start Page
1907
End Page
1914

Bactericidal activity of mast cells

Authors
Abraham, SN
MLA Citation
Abraham, SN. "Bactericidal activity of mast cells." Gastroenterology 107.3 (1994): 894--.
Source
scival
Published In
Gastroenterology
Volume
107
Issue
3
Publish Date
1994
Start Page
894-

Bactericidal activity of mast cells

Authors
Barrett, KE; Abraham, SN
MLA Citation
Barrett, KE, and Abraham, SN. "Bactericidal activity of mast cells." Gastroenterology 107.3 (1994): 893-894.
Source
scival
Published In
Gastroenterology
Volume
107
Issue
3
Publish Date
1994
Start Page
893
End Page
894

FimC is a periplasmic PapD-like chaperone that directs assembly of type 1 pili in bacteria.

Biogenesis of the type 1 pilus fiber in Escherichia coli requires the product of the fimC locus. We have demonstrated that FimC is a member of the periplasmic chaperone family. The deduced primary sequence of FimC shows a high degree of homology to PapD and fits well with the derived consensus sequence for periplasmic chaperones, predicting that it has an immunoglobulin-like topology. The chaperone activity of FimC was demonstrated by purifying a complex that FimC forms with the FimH adhesion. A fimC1 null allele could be complemented by the prototype member of the chaperone superfamily, PapD, resulting in the production of adhesive type 1 pili. The general mechanism of action of members of the chaperone superfamily was demonstrated by showing that the ability of PapD to assemble both P and type 1 pili was dependent on an invariant arginine residue (Arg-8), which forms part of a conserved subunit binding site in the cleft of PapD. We suggest that the conserved cleft is a subunit binding feature of all members of this protein family. These studies point out the general strategies used by Gram-negative bacteria to assemble adhesins into pilus fibers, allowing them to promote attachment to eukaryotic receptors.

Authors
Jones, CH; Pinkner, JS; Nicholes, AV; Slonim, LN; Abraham, SN; Hultgren, SJ
MLA Citation
Jones, CH, Pinkner, JS, Nicholes, AV, Slonim, LN, Abraham, SN, and Hultgren, SJ. "FimC is a periplasmic PapD-like chaperone that directs assembly of type 1 pili in bacteria." Proc Natl Acad Sci U S A 90.18 (September 15, 1993): 8397-8401.
PMID
8104335
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
90
Issue
18
Publish Date
1993
Start Page
8397
End Page
8401

Pilus and nonpilus bacterial adhesins: assembly and function in cell recognition.

Authors
Hultgren, SJ; Abraham, S; Caparon, M; Falk, P; St Geme, JW; Normark, S
MLA Citation
Hultgren, SJ, Abraham, S, Caparon, M, Falk, P, St Geme, JW, and Normark, S. "Pilus and nonpilus bacterial adhesins: assembly and function in cell recognition." Cell 73.5 (June 4, 1993): 887-901. (Review)
PMID
8098994
Source
pubmed
Published In
Cell
Volume
73
Issue
5
Publish Date
1993
Start Page
887
End Page
901

Neutrophil activation by nascent FimH subunits of type 1 fimbriae purified from the periplasm of Escherichia coli.

Previous studies of type 1 fimbriae of Escherichia coli have implicated FimH, a minor subunit, as the determinant of its mannose binding property. Structure-function analysis of FimH has not been possible because of the difficulty in obtaining adequate amounts of the subunit from type 1 fimbriae. We have obtained nascent FimH that has not been incorporated into the fimbrial structure from the periplasm of an E. coli strain expressing the cloned fimH gene. Nascently translocated FimH was initially degraded in the periplasm; however, when co-expressed with FimC, a putative fimbrial chaperone, the FimH molecules were stabilized and readily isolated from the periplasmic extract by fractionation on a sodium dodecyl sulfate-polyacrylamide gel followed by electroelution of the FimH band from the gel. The eluted protein was purified to homogeneity by affinity chromatography on a mannose-Sepharose column. Purified FimH displayed the same mannose-inhibitable binding to human neutrophils as type 1 fimbriated bacteria, including triggering an oxidative burst with concomitant release of reactive oxygen metabolites. In addition, inert microspheres coated with FimH, but not those coated with bovine serum albumin, were phagocytosed by neutrophils. These data provide direct evidence that FimH is the determinant on type 1 fimbriae which is responsible for mediating mannose-specific adherence and that isolated FimH is a potent activator of human neutrophils.

Authors
Tewari, R; MacGregor, JI; Ikeda, T; Little, JR; Hultgren, SJ; Abraham, SN
MLA Citation
Tewari, R, MacGregor, JI, Ikeda, T, Little, JR, Hultgren, SJ, and Abraham, SN. "Neutrophil activation by nascent FimH subunits of type 1 fimbriae purified from the periplasm of Escherichia coli." J Biol Chem 268.4 (February 5, 1993): 3009-3015.
PMID
8094080
Source
pubmed
Published In
The Journal of biological chemistry
Volume
268
Issue
4
Publish Date
1993
Start Page
3009
End Page
3015

T-cell-independent stimulation of immunoglobulin secretion in resting human B lymphocytes by the mannose-specific adhesin of Escherichia coli type 1 fimbriae.

Purified Escherichia coli type 1 fimbriae have been shown previously to stimulate T-cell-independent proliferation of human B lymphocytes. The response is mediated by the mannose-specific, lectin-like adhesin protein FimH. Here we show that type 1 fimbriae also stimulate immunoglobulin (Ig) secretion by B cells. The response was maximal at three days of culture and consisted predominantly of the IgM isotype. It was independent of serum components, T lymphocytes, monocytes, and natural killer cells. Highly purified resting B cells were induced to proliferate and secrete Ig in response to the fimbriae. The role of FimH in the response was shown by the failure of FimH- type 1 fimbriae to stimulate and by inhibition of the response with alpha-methyl mannoside. In light of the fact that carbohydrate-binding adhesins have been found on a wide variety of microorganisms, these studies suggest the possibility that responses of other cell types to other microbial adhesins will be discovered.

Authors
Ponniah, S; Abraham, SN; Endres, RO
MLA Citation
Ponniah, S, Abraham, SN, and Endres, RO. "T-cell-independent stimulation of immunoglobulin secretion in resting human B lymphocytes by the mannose-specific adhesin of Escherichia coli type 1 fimbriae." Infect Immun 60.12 (December 1992): 5197-5203.
PMID
1360450
Source
pubmed
Published In
Infection and immunity
Volume
60
Issue
12
Publish Date
1992
Start Page
5197
End Page
5203

Functional heterogeneity of type 1 fimbriae of Escherichia coli.

Escherichia coli and other members of the family Enterobacteriaceae express surface fibrillar structures, fimbriae, that promote bacterial adhesion to host receptors. Type 1 fimbriae possess a lectinlike component, FimH, that is commonly thought to cause binding to mannose-containing oligosaccharides of host receptors. Since adhesion of type 1 fimbriated organisms are inhibited by mannose, the reactions are described as mannose sensitive (MS). We have studied the adhesion of the type 1 fimbriated CSH-50 strain of E. coli (which expresses only type 1 fimbriae) to fibronectin (FN). E. coli CSH-50 does not bind detectable amounts of soluble FN but adheres well to immobilized plasma or cellular FN. This adhesion was inhibited by mannose-containing saccharides. By using purified domains of FN, it was found that E. coli CSH-50 adheres primarily to the amino-terminal and gelatin-binding domains, only one of which is glycosylated, in an MS fashion. Binding of the mannose-specific lectin concanavalin A to FN and ovalbumin was eliminated or reduced, respectively, by incubation with periodate or endoglycosidase. Adhesion of E. coli CSH-50 to ovalbumin was reduced by these treatments, but adhesion to FN was unaffected. E. coli CSH-50 also adheres to a synthetic peptide copying a portion of the amino-terminal FN domain (FNsp1) in an MS fashion. Purified CSH-50 fimbriae bound to immobilized FN and FNsp1 in an MS fashion and inhibited adhesion of intact organisms. However, fimbriae purified from HB101 (pPKL4), a recombinant strain harboring the entire type 1 fim gene locus and expressing functional type 1 fimbriae, neither bound to FN or FNsp1 nor inhibited E. coli adhesion to immobilized FN or FNsp1. These novel findings suggest that there are two forms of type 1 MS fimbriae. One form exhibits only the well-known MS lectinlike activity that requires a substratum of mannose-containing glycoproteins. The other form exhibits not only the MS lectinlike activity but also binds to nonglycosylated regions of proteins in an MS manner.

Authors
Sokurenko, EV; Courtney, HS; Abraham, SN; Klemm, P; Hasty, DL
MLA Citation
Sokurenko, EV, Courtney, HS, Abraham, SN, Klemm, P, and Hasty, DL. "Functional heterogeneity of type 1 fimbriae of Escherichia coli." Infect Immun 60.11 (November 1992): 4709-4719.
PMID
1356930
Source
pubmed
Published In
Infection and immunity
Volume
60
Issue
11
Publish Date
1992
Start Page
4709
End Page
4719

Glycerol-induced unraveling of the tight helical conformation of Escherichia coli type 1 fimbriae.

Glycerol was found to unravel the helical conformation of Escherichia coli type 1 fimbriae without appreciable depolymerization. The linearized fimbrial polymers have a diameter of 2 nm, react strongly with a monoclonal antibody directed at an inaccessible epitope on native fimbriae, and display greater mannose-binding activity and trypsin sensitivity than native fimbriae. Removal of glycerol by dialysis results in spontaneous reassembly of the linear polymers into structures morphologically, antigenically, and functionally indistinguishable from native fimbriae.

Authors
Abraham, SN; Land, M; Ponniah, S; Endres, R; Hasty, DL; Babu, JP
MLA Citation
Abraham, SN, Land, M, Ponniah, S, Endres, R, Hasty, DL, and Babu, JP. "Glycerol-induced unraveling of the tight helical conformation of Escherichia coli type 1 fimbriae." J Bacteriol 174.15 (August 1992): 5145-5148.
PMID
1352770
Source
pubmed
Published In
Journal of bacteriology
Volume
174
Issue
15
Publish Date
1992
Start Page
5145
End Page
5148

The 9-kDa hydrophobic protein encoded at the 3′ end of the porcine transmissible gastroenteritis coronavirus genome is membrane-associated

The open reading frame potentially encoding a 78 amino acid, 9101 Da hydrophobic protein (HP) and, mapping at the 3′ end of the porcine transmissible gastroenteritis coronavirus (TGEV) genome, was shown to be expressed during virus replication. The cloned HP gene was placed in a plasmid under control of the T7 RNA polymerase promoter and in vitro translation of transcripts generated in vitro yielded a 9.1-kDa protein that was immunoprecipitable with porcine hyperimmune anti-TGEV serum. Antiserum raised in rabbits against a 31 amino acid synthetic polypeptide that represented the central hydrophilic region of HP specifically immunoprecipitated HP from TGEV-infected cells. HP was further shown to become associated with microsomal membranes during synthesis in vitro and was found to be closely associated with the endoplasmic reticulum and cell surface membranes in infected cells. The intracellular location of HP suggests that it may play a role in the membrane association of replication complexes or in virion assembly. © 1992.

Authors
Tung, FYT; Abraham, S; Sethna, M; Hung, S-L; Sethna, P; Hogue, BG; Brian, DA
MLA Citation
Tung, FYT, Abraham, S, Sethna, M, Hung, S-L, Sethna, P, Hogue, BG, and Brian, DA. "The 9-kDa hydrophobic protein encoded at the 3′ end of the porcine transmissible gastroenteritis coronavirus genome is membrane-associated." Virology 186.2 (1992): 676-683.
Source
scival
Published In
Virology
Volume
186
Issue
2
Publish Date
1992
Start Page
676
End Page
683

Fragmentation of Escherichia coli type 1 fimbriae exposes cryptic D-mannose-binding sites.

Cells of the gram-negative bacterium Escherichia coli are able to attach to various host cells by means of a mannose-specific adhesin associated with type 1 fimbriae. Here we show that fragmentation of type 1 fimbriae by freezing and thawing results in increased mannose-binding activity as demonstrated by increased hemagglutination, increased stimulation of human lymphocyte proliferation, and increased binding of the mannose-containing enzyme horseradish peroxidase. Increased activity in all three assays was mannose sensitive and was not exhibited by FimH- mutant type 1 fimbriae lacking the adhesin. Scatchard analysis of the data from peroxidase binding assays showed that unfrozen and frozen fimbriae contain binding sites displaying two classes of affinity. Frozen and thawed fimbriae expressed an increase in the number of high-affinity binding sites. These results show that fragmentation of the fimbrial structure exposes cryptic mannose-binding activity associated with type 1 fimbriae, presumably that of internally located adhesin molecules. Our data support earlier observations that adhesin moieties of type 1 fimbriae are located both at the tips and at intervals along the length of the fimbriae. In addition, our data suggest that only the adhesin moieties that are located at the fimbrial tips are functional in binding mannose. Adhesins located along the length of the fimbriae have their mannose-binding activity buried within the fimbrial structure and hence are not functional. We propose an updated model for the structure of type 1 fimbriae that is in agreement with the above observations.

Authors
Ponniah, S; Endres, RO; Hasty, DL; Abraham, SN
MLA Citation
Ponniah, S, Endres, RO, Hasty, DL, and Abraham, SN. "Fragmentation of Escherichia coli type 1 fimbriae exposes cryptic D-mannose-binding sites." J Bacteriol 173.13 (July 1991): 4195-4202.
PMID
1676398
Source
pubmed
Published In
Journal of bacteriology
Volume
173
Issue
13
Publish Date
1991
Start Page
4195
End Page
4202

Isolation and characterization of a 180-kiloDalton salivary glycoprotein which mediates the attachment of Actinomyces naeslundii to human buccal epithelial cells.

The adherence of Actinomyces naeslundii to human buccal mucosa is mediated by specific interactions between the bacterial cell surface fimbriae and complementary beta-linked galactoside receptors on the epithelial cell surface. The buccal mucosa and the bacteria that colonize its surface are constantly bathed in saliva. Several salivary components are thought to play an important role in modulating adhesive interactions between oral bacteria and the buccal epithelium. We have observed that pretreatment of isolated buccal epithelial cells (BEC) with human parotid saliva increased the attachment of three different strains of A. naeslundii. By employing affinity chromatography, ion-exchange and high-pressure liquid chromatographic techniques we have isolated a 180 kDa A. naeslundii-binding salivary glycoprotein (An-SPG). This salivary glycoprotein was capable of mediating separate but specific binding interactions with A. naeslundii and BEC. Pretreatment of BEC with increasing amounts of An-SGP resulted in a corresponding increase in the attachment of A. naeslundii. The adherence of A. naeslundii to An-SGP-coated BEC is sensitive to the same inhibitors previously shown to block adherence of A. naeslundii to uncoated BEC, namely lactose- and galactosyl-binding lectins. When a solubilized extract of freshly isolated and washed BEC was reacted on a Western blot with antibodies to An-SGP, a prominent 180 kDa immunoreactive band was detected. Furthermore, the immunoreactive component was demonstrated on the BEC surface when assayed by immunofluorescence using An-SGP-specific antibodies, suggesting that An-SGP or a protein structurally and immunologically identical to the isolated glycoprotein is present on BEC.

Authors
Babu, JP; Dabbous, MK; Abraham, SN
MLA Citation
Babu, JP, Dabbous, MK, and Abraham, SN. "Isolation and characterization of a 180-kiloDalton salivary glycoprotein which mediates the attachment of Actinomyces naeslundii to human buccal epithelial cells." J Periodontal Res 26.2 (March 1991): 97-106.
PMID
1826530
Source
pubmed
Published In
Journal of Periodontal Research
Volume
26
Issue
2
Publish Date
1991
Start Page
97
End Page
106

Chaperone-assisted assembly and molecular architecture of adhesive pili.

The assembly of bacterial pili as exemplified here by P and type 1 pili of E. coli is a complex process involving specific molecular interactions between structural and chaperone proteins. The assembly process occurs postsecretionally, i.e. after the subunits are translocated across the cytoplasmic membrane. In a single cell, hundreds of thousands of interactive subunits are typically surface localized and assembled into pili. Periplasmic chaperones are generally required to bind to the interactive subunits and partition them into assembly-competent complexes. The binding of the chaperone to the subunits apparently protects the interactive surfaces and prevents them from aggregating at the wrong time and place within the cell. Pili are most likely assembled into linear polymers that package into right-handed helices after their translocation through specific outer-membrane channels. Each pilus filament is a quaternary assembly of the structural subunit and several minor subunits including the adhesin moiety. Although the assembly and organization of P and type 1 pili are very similar, there are some notable differences. For example, the P pilus adhesin is located exclusively at the tips of the pilus filament and forms part of a morphologically distinct structure. In contrast, the adhesion moiety of type 1 pili is inserted into the pilus filament at intervals, but only the adhesin molecule exposed at the pilus tip is functional. The variability in isoreceptor recognition amongst P pili has been solely ascribed to structural differences in the respective adhesin molecules, whereas in type 1 pili, variability in binding specificity has been attributed to the pilus filament that influences the conformation of the adhesin moiety. Less is known about the structure or assembly of type 4 pili, which are a unique class of pili expressed by several different species of gram-negative bacteria. The phase variation of the pilC assembly gene in N. gonorrheae to the off state results in the accumulation of unassembled subunits toxic to the cells. This process exerts a strong selection pressure on the cells that triggers alterations in the pilin structural gene. Thus, antigenic variation of pili in this organism may be regulated at the level of assembly. Finally, the concept of periplasmic chaperones in postsecretional assembly is most likely a general phenomenon in the biology of gram-negative bacteria. The investigations of pilus assembly will continue to provide insight into the details of how macromolecular assembly reactions are coordinated in the bacterial cell and how the regulation of assembly genes can profoundly affect biological processes.

Authors
Hultgren, SJ; Normark, S; Abraham, SN
MLA Citation
Hultgren, SJ, Normark, S, and Abraham, SN. "Chaperone-assisted assembly and molecular architecture of adhesive pili." Annu Rev Microbiol 45 (1991): 383-415. (Review)
PMID
1683764
Source
pubmed
Published In
Annual Review of Microbiology
Volume
45
Publish Date
1991
Start Page
383
End Page
415
DOI
10.1146/annurev.mi.45.100191.002123

Colonial morphology of staphylococci on Memphis agar: phase variation of slime production, resistance to beta-lactam antibiotics, and virulence.

The growth of Staphylococcus epidermidis sensu stricto and Staphylococcus saprophyticus on Memphis agar yielded up to 6 morphotypes with each strain. With S. epidermidis, one morphotype produced slime (rho) but became non-slime-producing (epsilon) at a high frequency. The slime-producing rho variants were methicillin-resistant and more virulent than methicillin-susceptible epsilon variants in an endocarditis model. With S. saprophyticus, phase variation was of higher frequency. Nitrosoguanidine mutagenesis produced a stable blue epsilon form that was more virulent than the parent in a mouse model of urinary tract infection. Mutants with the blue epsilon phenotype differed from gold epsilon parents in a variety of phenotypic properties, including increased resistance to oxacillin. These staphylococcal species have a high frequency of phase variation: Phase variants differ in antibiotic resistance and virulence, which is only partially correlated with suggested virulence factors such as slime production.

Authors
Christensen, GD; Baddour, LM; Madison, BM; Parisi, JT; Abraham, SN; Hasty, DL; Lowrance, JH; Josephs, JA; Simpson, WA
MLA Citation
Christensen, GD, Baddour, LM, Madison, BM, Parisi, JT, Abraham, SN, Hasty, DL, Lowrance, JH, Josephs, JA, and Simpson, WA. "Colonial morphology of staphylococci on Memphis agar: phase variation of slime production, resistance to beta-lactam antibiotics, and virulence." J Infect Dis 161.6 (June 1990): 1153-1169.
PMID
2345296
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
161
Issue
6
Publish Date
1990
Start Page
1153
End Page
1169

Structure and expression of the bovine coronavirus hemagglutinin protein

Authors
Kienzle, TE; Abraham, S; Hogue, BG; Brian, DA
MLA Citation
Kienzle, TE, Abraham, S, Hogue, BG, and Brian, DA. "Structure and expression of the bovine coronavirus hemagglutinin protein." Advances in Experimental Medicine and Biology 276 (1990): 95-102.
Source
scival
Published In
Advances in human genetics
Volume
276
Publish Date
1990
Start Page
95
End Page
102

Deduced sequence of the bovine coronavirus spike protein and identification of the internal proteolytic cleavage site

The sequence of the spike (also called peplomer or E2) protein gene of the Mebus strain of bovine coronavirus (BCV) was obtained from cDNA clones of genomic RNA. The gene sequence predicts a 150,825 mol wt apoprotein of 1363 amino acids having an N-terminal hydrophobic signal sequence of 17 amino acids, 19 potential N-linked glycosylation sites, a hydrophobic anchor sequence of approximately 17 amino acids near the C terminus, and a hydrophilic cysteinerich C terminus of 35 amino acids. An internal LysArgArgSerArgArg sequence predicts a protease cleavage site between amino acids 768 and 769 that would separate the S apoprotein into S1 and S2 segments of 85690 and 65153 mol wt, respectively. Amino terminal amino acid sequencing of the virion-derived gp100 spike subunit confirmed the location of the predicted cleavage site, and established that gp120 and gp100 are the glycosylated virion forms of the S1 and S2 subunits, respectively. Sequence comparisons between BCV and the antigenically related mouse hepatitis coronavirus revealed more sequence divergence in the putative knob region of the spike protein (S1) than in the stem region (S2). © 1990.

Authors
Abraham, S; Kienzle, TE; Lapps, W; Brian, DA
MLA Citation
Abraham, S, Kienzle, TE, Lapps, W, and Brian, DA. "Deduced sequence of the bovine coronavirus spike protein and identification of the internal proteolytic cleavage site." Virology 176.1 (1990): 296-301.
Source
scival
Published In
Virology
Volume
176
Issue
1
Publish Date
1990
Start Page
296
End Page
301

Sequence and expression analysis of potential nonstructural proteins of 4.9, 4.8, 12.7, and 9.5 kDa encoded between the apike and membrane protein genes of the bovine coronavirus

The nucleotide sequence between the spike and membrane protein genes in the bovine coronavirus (BCV) genome was determined by sequencing cDNA clones of the genome, and open reading frames potentially encoding proteins of 4.9, 4.8, 12.7, and 9.5 kDa, in that order, were identified. The 4.9- and 4.8-kDa proteins appear to be vestiges of an 11-kDa protein for which a single nucleotide deletion event in the central part of the gene gave rise to a stop codon. The consensus CYAAAC sequence precedes the 4.9-, 12.7-, and 9.5-kDa ORFs and predicts that transcription will start from each of these sites. Northern analyses using sequence-specific probes and oligo(dT)-selected RNA demonstrated that the predicted transcripts are made, and that these correspond to mRNAs 4, 5, and 5-1. BCV mRNA 4 appears to be a counterpart to mouse hepatitis virus (MHV) mRNA 4 which, in the MHV JHM strain, encodes the putative 15.2-kDa nonstructural protein. BCV mRNAs 5 and 5-1 appear to be used for the synthesis of the 12.7- and 9.5-kDa proteins, respectively, which demonstrates a pattern of expression strikingly different from that utilized by MHV. MHV makes its homologs of the 12.7- and 9.5-kDa proteins from the single mRNA 5. In vitro translation analyses demonstrated that the BCV 9.5-kDa protein, unlike its MHV counterpart, is poorly made from downstream initiation of translation. Thus, from a comparison between BCV and MHV we find evolutionary evidence for the importance of the CYAAAC sequence in regulating coronavirus transcription. © 1990.

Authors
Abraham, S; Kienzle, TE; Lapps, WE; Brian, DA
MLA Citation
Abraham, S, Kienzle, TE, Lapps, WE, and Brian, DA. "Sequence and expression analysis of potential nonstructural proteins of 4.9, 4.8, 12.7, and 9.5 kDa encoded between the apike and membrane protein genes of the bovine coronavirus." Virology 177.2 (1990): 488-495.
Source
scival
Published In
Virology
Volume
177
Issue
2
Publish Date
1990
Start Page
488
End Page
495

Structure and orientation of expressed bovine coronavirus hemagglutinin-esterase protein

The sequence of the hemagglutinin-esterase (HE) gene for the Mebus strain of bovine coronavirus was obtained from cDNA clones, and its deduced product is a 47,700-kilodalton apoprotein of 424 amino acids. Expression of the HE protein in vitro in the presence of microsomes revealed N-terminal signal peptide cleavage and C-terminal anchorage but not disulfide-linked dimerization. Dimerization was observed only after expression in vivo, during which HE was also transported to the cell surface.

Authors
Kienzle, TE; Abraham, S; Hogue, BG; Brian, DA
MLA Citation
Kienzle, TE, Abraham, S, Hogue, BG, and Brian, DA. "Structure and orientation of expressed bovine coronavirus hemagglutinin-esterase protein." Journal of Virology 64.4 (1990): 1834-1838.
Source
scival
Published In
Journal of virology
Volume
64
Issue
4
Publish Date
1990
Start Page
1834
End Page
1838

Mitogenic stimulation of human B lymphocytes by the mannose-specific adhesin on Escherichia coli type 1 fimbriae.

Escherichia coli type 1 fimbriae contain in association with the major structural protein a lectin-like adhesin moiety that mediates attachment of E. coli to mannose-containing receptors on the surface of host cells. We have investigated the lymphocyte mitogenic activity of this mannose-specific adhesin by comparing the ability of purified wild type type 1 fimbriae containing the adhesin and mutant type 1 fimbriae lacking the adhesin to stimulate proliferation in human lymphocytes. Both fimbriae stimulated a peak of proliferation at 8 days whereas only the wild type fimbriae stimulated an additional peak of proliferation occurring at 3 days. Proliferation at 3 days but not at 8 days could be blocked by the addition of alpha-methyl-D-mannoside. Neonatal lymphocytes from umbilical cord blood responded to both wild type and mutant fimbriae in a fashion similar to adult cells. Stimulation of separated T and non-T cell populations indicated that the proliferation seen at 3 days was solely due to non-T cells whereas the 8-day response was due to T cell proliferation. The addition of gamma-irradiated T cells did not appear to enhance the 3-day response of the non-T cells. However, the 8-day response by T cells was dependent on the presence of gamma-irradiated non-T cells. In cultures of unseparated cells, wild type fimbriae stimulated more than 75% of the B cells to enter the S and G2 phase at 3 days whereas at 8 days cycling T cells were present in both wild type and mutant fimbriae-stimulated cultures. Taken together, our observations suggest that the adhesin molecule stimulates a polyclonal mitogenic response in B cells that peaks at 3 days, and other structural components of the fimbriae are responsible for evoking an 8-day (probably immune) response in T cells.

Authors
Ponniah, S; Abraham, SN; Dockter, ME; Wall, CD; Endres, RO
MLA Citation
Ponniah, S, Abraham, SN, Dockter, ME, Wall, CD, and Endres, RO. "Mitogenic stimulation of human B lymphocytes by the mannose-specific adhesin on Escherichia coli type 1 fimbriae." J Immunol 142.3 (February 1, 1989): 992-998.
PMID
2563273
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
142
Issue
3
Publish Date
1989
Start Page
992
End Page
998

Conservation of the D-mannose-adhesion protein among type 1 fimbriated members of the family Enterobacteriaceae.

A variety of genera and species of the family Enterobacteriaceae bear surface fimbriae that enable them to bind to D-mannose residues on eukaryotic cells. Until recently, it was thought that the D-mannose binding site was located in the major structural subunit (FimA), of relative molecular mass (Mr) 17,000 (17 K), of these organelles in Escherichia coli. New evidence indicates that this binding site resides instead in a minor protein Mr 28-31 K (FimH) located at the tips and at long intervals along the length of the fimbriae, and is reminiscent of the minor tip adhesion proteins of pyelonephritis-associated pili (Pap) and S fimbriae. In contrast to the antigenic heterogeneity of the major FimA subunit, the antigenic structure of FimH is conserved among different strains of E. coli. Here, we report an even broader conservation of this minor adhesion protein extending to other genera and species of type 1 fimbriated Enterobacteriaceae. Our results may have implications for the development of broadly protective vaccines against Gram-negative bacillary infections in animals and perhaps in man.

Authors
Abraham, SN; Sun, D; Dale, JB; Beachey, EH
MLA Citation
Abraham, SN, Sun, D, Dale, JB, and Beachey, EH. "Conservation of the D-mannose-adhesion protein among type 1 fimbriated members of the family Enterobacteriaceae." Nature 336.6200 (December 15, 1988): 682-684.
PMID
2904657
Source
pubmed
Published In
Nature
Volume
336
Issue
6200
Publish Date
1988
Start Page
682
End Page
684
DOI
10.1038/336682a0

Bacterial adherence. Adhesin receptor-mediated attachment of pathogenic bacteria to mucosal surfaces.

Pathogenic bacteria adhere to and colonize mucosal surfaces of the susceptible host in a highly selective manner. After the organisms penetrate the nonspecific mechanical and cleansing forces, ligands (or adhesins) on the surface of the bacteria interact in a lock-and-key fashion with complementary receptors on mucosal surfaces of the host. The adhesins are usually composed of proteins in the form of fimbriae or fibrillae and the receptors of glycolipids or glycoproteins. At the epithelial cell surfaces, two classic examples of bacterial adherence are the lipoteichoic acid-mediated attachments of group A streptococcal and the type 1 fimbriae-mediated attachment of Escherichia coli. In group A streptococci, the adhesin, lipoteichoic acid (LTA), is anchored to a protein(s) on the surface of the bacterial cells and interacts through its lipid moiety with fibronectin molecules deposited on and bound to the epithelial cells. In type 1 fimbriated E. coli, a minor 29-kDa protein located at the tip of the fimbriae interacts with D-mannose residues of glycoprotein receptors on host cells. Similar adhesin-receptor interactions have now been described for a number of pathogenic microbial agents, and undoubtedly play a central role in the early steps of the infectious process.

Authors
Beachey, EH; Giampapa, CS; Abraham, SN
MLA Citation
Beachey, EH, Giampapa, CS, and Abraham, SN. "Bacterial adherence. Adhesin receptor-mediated attachment of pathogenic bacteria to mucosal surfaces." Am Rev Respir Dis 138.6 Pt 2 (December 1988): S45-S48.
PMID
2904779
Source
pubmed
Published In
American Review of Respiratory Disease
Volume
138
Issue
6 Pt 2
Publish Date
1988
Start Page
S45
End Page
S48
DOI
10.1164/ajrccm/138.6_Pt_2.S45

Influence of berberine sulfate on synthesis and expression of Pap fimbrial adhesin in uropathogenic Escherichia coli.

We investigated the influence of berberine sulfate, an ancient Chinese antibiotic, upon the adhesion of uropathogenic Escherichia coli to erythrocytes and epithelial cells. Although berberine sulfate in increasing concentrations had no effect on bacterial growth or on the synthesis of major outer membrane proteins of the E. coli organisms, it increasingly blocked adhesion. The decreased adhesion was accompanied by a reduction in the synthesis of fimbrial subunits and in the expression of assembled fimbriae. These results suggest that the anti-infectious activity of berberine sulfate in E. coli-induced urinary tract infections may be mediated by the selective suppression of the synthesis and assembly of fimbriae by uropathogenic organisms.

Authors
Sun, D; Abraham, SN; Beachey, EH
MLA Citation
Sun, D, Abraham, SN, and Beachey, EH. "Influence of berberine sulfate on synthesis and expression of Pap fimbrial adhesin in uropathogenic Escherichia coli." Antimicrob Agents Chemother 32.8 (August 1988): 1274-1277.
PMID
2903716
Source
pubmed
Published In
Antimicrobial agents and chemotherapy
Volume
32
Issue
8
Publish Date
1988
Start Page
1274
End Page
1277

Hyperadhesive mutant of type 1-fimbriated Escherichia coli associated with formation of FimH organelles (fimbriosomes).

The relationships of the genes and gene-products mediating D-mannose-specific attachment of type 1 fimbriae of Escherichia coli to eucaryotic cells were investigated by deletion mutation analysis of recombinant plasmid pSH2, which carries the genetic information for the synthesis and expression of functional type 1 fimbriae. Mutant pUT2004 was derived by a deletion remote from the structural gene encoding the 17-kilodalton (kDa) subunit protein of type 1 fimbriae. Phenotypically, the mutant demonstrated an eightfold-higher mannose-specific hemagglutination titer than the parent strain. On electron microscopy, the mutant strain expressed the same number of fimbriae as the parent strain. However, numerous 10-nm-diameter rounded structures (fimbriosomes) were observed both closely associated with fimbriae and in the culture medium. Fimbriosomes isolated from the medium agglutinated guinea pig erythrocytes in a mannose-sensitive manner. Dissociation of the fimbriosomes yielded a single 29-kDa protein, as demonstrated by sodium dodecyl sulfate gel electrophoresis. Antibodies raised against fimbriosomes reacted with a 29-kDa protein on immunoelectroblots of dissociated type 1 fimbriae and also blocked the adherence of other strains of type 1 fimbriated E. coli to eucaryotic cells. These findings suggest that the enhanced adhesive properties of the mutant pUT2004 strain are associated with overproduction of the 29-kDa FimH in the form of fimbriosomes which contain the determinant of the D-mannose-sensitive adhesion of type 1 fimbriae.

Authors
Abraham, SN; Goguen, JD; Beachey, EH
MLA Citation
Abraham, SN, Goguen, JD, and Beachey, EH. "Hyperadhesive mutant of type 1-fimbriated Escherichia coli associated with formation of FimH organelles (fimbriosomes)." Infect Immun 56.5 (May 1988): 1023-1029.
PMID
2895738
Source
pubmed
Published In
Infection and immunity
Volume
56
Issue
5
Publish Date
1988
Start Page
1023
End Page
1029

Isolation and characterization of a receptor for type 1 fimbriae of Escherichia coli from guinea pig erythrocytes.

The adhesion of Escherichia coli to eukaryotic cells is mediated by proteinaceous surface appendages called fimbriae and complementary receptors on host cells. Although type 1 fimbriae, which contain a D-mannose-reactive lectin, have been well studied little is known about the binding mechanism of isolated fimbriae to individual cell receptors. This report describes the isolation and purification of a guinea pig erythrocyte receptor for type 1 fimbriae. Erythrocyte membranes were dissolved in 0.5% Triton X-100 and the receptor isolated and purified by affinity chromatography using type 1 fimbriae immobilized on Sepharose. The 65-kDa receptor, which inhibits the agglutination of guinea pig erythrocytes by type 1 fimbriated E. coli, has a pI of 8.5-8.7, and binds concanavalin A and type 1 fimbriae in a dose-dependent and saturable manner. The fimbrial binding activity of the receptor was reduced when treated with sodium metaperiodate, endoglycosidase H, trypsin, and V8 protease, suggesting the isolated receptor is a glycoprotein with N-linked carbohydrate units. Isolated type 1 fimbriae inhibited the binding of fimbriated E. coli to purified receptor in a dose- and time-related fashion. The calculated binding affinity was 6 X 10(6) M-1, a value consistent with the low binding affinity expected from previous studies of the agglutination of guinea pig erythrocytes by isolated type 1 fimbriae.

Authors
Giampapa, CS; Abraham, SN; Chiang, TM; Beachey, EH
MLA Citation
Giampapa, CS, Abraham, SN, Chiang, TM, and Beachey, EH. "Isolation and characterization of a receptor for type 1 fimbriae of Escherichia coli from guinea pig erythrocytes." J Biol Chem 263.11 (April 15, 1988): 5362-5367.
PMID
2895767
Source
pubmed
Published In
The Journal of biological chemistry
Volume
263
Issue
11
Publish Date
1988
Start Page
5362
End Page
5367

Binding of bacteria to mucosal surfaces.

Authors
Abraham, SN; Beachey, EH
MLA Citation
Abraham, SN, and Beachey, EH. "Binding of bacteria to mucosal surfaces." Monogr Allergy 24 (1988): 38-43.
PMID
2896296
Source
pubmed
Published In
Monographs in allergy
Volume
24
Publish Date
1988
Start Page
38
End Page
43

Bacterial adherence. Adhesin receptor-mediated attachment of pathogenic bacteria to mucosal surfaces

Pathogenic bacteria adhere to and colonize mucosal surfaces of the susceptible host in a highly selective manner. After the organisms penetrate the nonspecific mechanical and cleansing forces, ligands (or adhesins) on the surface of the bacteria interact in a lock-and-key fashion with complementary receptors on mucosal surfaces of the host. The adhesins are usually composed of proteins in the form of fimbriae or fibrillae and the receptors of glycolipids or glycoproteins. At the epithelial cell surfaces, two classic examples of bacterial adherence are the lipoteichoic acid-mediated attachments of group A streptococcal and the type 1 fimbriae-mediated attachment of Escherichia coli. In group A streptococci, the adhesin, lipoteichoic acid (LTA), is anchored to a protein(s) on the surface of the bacterial cells and interacts through its lipid moiety with fibronectin molecules deposited on and bound to the epithelial cells. In type 1 fimbriated E. coli, a minor 29-kDa protein located at the tip of the fimbriae interacts with D-mannose residues of glycoprotein receptors on host cells. Similar adhesin-receptor interactions have nown been described for a number of pathogenic microbial agents, and undoubtedly play a central role in the early steps of the infectious process.

Authors
Beachey, EH; Giampapa, CS; Abraham, SN
MLA Citation
Beachey, EH, Giampapa, CS, and Abraham, SN. "Bacterial adherence. Adhesin receptor-mediated attachment of pathogenic bacteria to mucosal surfaces." American Review of Respiratory Disease 138.6 II (1988): S45-S48.
Source
scival
Published In
American Review of Respiratory Disease
Volume
138
Issue
6 II
Publish Date
1988
Start Page
S45
End Page
S48

Identification of two ancillary subunits of Escherichia coli type 1 fimbriae by using antibodies against synthetic oligopeptides of fim gene products.

We have chemically synthesized oligopeptides corresponding to the NH2-terminal stretch of two gene products, designated FimG and FimH, of the fim gene cluster of Escherichia coli. These synthetic peptides, designated S-T1FimG(1-16) and S-T1FimH(1-25)C, evoked antibodies in rabbits that reacted with 14- and 29-kilodalton subunits, respectively, of dissociated fimbriae encoded by the recombinant plasmid pSH2 carrying the genetic information for the synthesis and expression of functional type 1 fimbriae. Neither of these fimbrial proteins was detected in dissociated fimbrial preparations from nonadhesive E. coli cells carrying the mutant plasmid pUT2002, containing a restriction site-specific deletion of fimG and fimH. Anti-S-T1FimH(1-25)C inhibited the adherence of type 1 fimbriated E. coli to epithelial cells. Immunoelectron microscopy revealed that anti-S-T1FimH(1-25)C, but not anti-S-T1FimG(1-16), bound to intact type 1 fimbriae of E. coli at the fimbrial tips and at long intervals along the fimbrial filaments. Anti-S-T1FimG(1-16) appeared to be directed at epitopes not accessible on the intact fimbriae and consequently failed to bind to intact fimbriae or to block fimbrial attachment. Our results suggest that the fimG and fimH gene products are components of type 1 fimbriae and that FimH may be the tip adhesin mediating the binding of type 1 fimbriated E. coli to D-mannose residues on mucosal surfaces.

Authors
Abraham, SN; Goguen, JD; Sun, D; Klemm, P; Beachey, EH
MLA Citation
Abraham, SN, Goguen, JD, Sun, D, Klemm, P, and Beachey, EH. "Identification of two ancillary subunits of Escherichia coli type 1 fimbriae by using antibodies against synthetic oligopeptides of fim gene products." J Bacteriol 169.12 (December 1987): 5530-5536.
PMID
2890622
Source
pubmed
Published In
Journal of bacteriology
Volume
169
Issue
12
Publish Date
1987
Start Page
5530
End Page
5536

Assembly of a chemically synthesized peptide of Escherichia coli type 1 fimbriae into fimbria-like antigenic structures.

Escherichia coli type 1 fimbriae are composed of subunits, each of which comprises 158 amino acids. We synthesized a copy of a 13-residue peptide, located near the NH2 terminus of the fimbrial subunit, that assumed some of the properties of type 1 fimbriae. At pH 5.5 the synthetic peptide autoassembled into fibrillar structures that resembled type 1 fimbriae except that they appeared less rigid and rodlike. A quaternary structure-specific monoclonal antibody against type 1 fimbriae recognized the synthetic peptide in the assembled but not the unassembled state. Furthermore, when the synthetic peptide was injected in its fimbrial conformation into rabbits, it evoked antibodies that reacted with type 1 fimbriae isolated from E. coli.

Authors
Abraham, SN; Beachey, EH
MLA Citation
Abraham, SN, and Beachey, EH. "Assembly of a chemically synthesized peptide of Escherichia coli type 1 fimbriae into fimbria-like antigenic structures." J Bacteriol 169.6 (June 1987): 2460-2465.
PMID
2884209
Source
pubmed
Published In
Journal of bacteriology
Volume
169
Issue
6
Publish Date
1987
Start Page
2460
End Page
2465

Use of monoclonal antibodies to probe subunit- and polymer-specific epitopes of 987P fimbriae of Escherichia coli.

The relationship between the structure and biological function of 987P fimbriae of a strain of enterotoxigenic Escherichia coli (O9:K103:H-) from piglets was investigated. A set of four monoclonal antibodies was prepared from the spleen cells of mice immunized with isolated 987P fimbriae. Antibodies E11, D5, and C3, but not G10, reacted in enzyme-linked immunosorbent assays with 987P fimbriae-bearing E. coli. Electron microscopy showed that E11 and D5 reacted in a discrete periodic pattern forming a spiral motif along the length of the fimbriae. The results of enzyme-linked immunosorbent assays were in agreement with these results; antibodies E11 and D5 reacted at a high dilution (1:12,000) with native fimbriae on the surface of E. coli, whereas antibody C3 reacted at an intermediate dilution (1:3,000) and G10 failed to react at all (less than 1:250). In contrast, C3 and G10 reacted at a dilution of 1:3,276,000 with the fimbrial subunits derived by treating the isolated fimbriae with 6 M guanidine hydrochloride, whereas E11 and D5 reacted with the subunits at much lower dilutions of 1:800 and 1:6,400, respectively. Moreover, fimbriae reassembled from the subunits regained reactivity with antibodies D5 and E11, indicating that these antibodies are directed against quaternary conformational epitopes. Only the three antibodies (D5, E11, and C3) that recognized epitopes accessible on intact fimbriae were able to efficiently block the adhesion of 987P fimbriated E. coli to piglet enterocytes. These results indicate that certain epitopes of 987P fimbriae are dependent on quaternary structural conformation, whereas others are present on monomeric subunits; some of the latter appear to remain accessible on fully assembled fimbriae.

Authors
Schifferli, DM; Abraham, SN; Beachey, EH
MLA Citation
Schifferli, DM, Abraham, SN, and Beachey, EH. "Use of monoclonal antibodies to probe subunit- and polymer-specific epitopes of 987P fimbriae of Escherichia coli." Infect Immun 55.4 (April 1987): 923-930.
PMID
2881894
Source
pubmed
Published In
Infection and immunity
Volume
55
Issue
4
Publish Date
1987
Start Page
923
End Page
930

Interaction of a 60-kilodalton D-mannose-containing salivary glycoprotein with type 1 fimbriae of Escherichia coli.

A 60-kilodalton glycoprotein previously isolated and purified from human saliva (J. B. Babu, E. H. Beachey, D. L. Hasty, and W. A. Simpson, Infect. Immun. 51: 405-413, 1986) was found to interact with type 1 fimbriae and prevent adhesion of type 1 fimbriated Escherichia coli to animal cells in a D-mannose-sensitive manner. Purified salivary glycoprotein agglutinated type 1 fimbriated E. coli and, at subagglutinating concentrations, blocked the ability of type 1 fimbriated E. coli to attach to human buccal epithelial cells or agglutinate guinea pig erythrocytes. Both interactions were inhibited by alpha-methyl-D-mannoside but not by alpha-methyl-D-glucoside. Complexing of the glycoprotein to type 1 fimbriae was demonstrated by molecular sieve chromatography and modified Western blots. When mixed with type 1 fimbriae, the radiolabeled salivary glycoprotein coeluted with type 1 fimbriae from a column of Sepharose 4B. When blotted from a sodium dodecyl sulfate gel to nitrocellulose sheets, the glycoprotein interacted directly with type 1 fimbriae applied to the blots. Both of the latter interactions also were blocked by alpha-methyl-D-mannoside but not by alpha-methyl-D-glucoside. Chemical modification of the glycoprotein with sodium metaperiodate abolished its ability to interact with isolated type 1 fimbriae or type 1 fimbriated E. coli. These results suggest that the carbohydrate moiety of the 60-kilodalton glycoprotein serves as a receptor for type 1 fimbriae in the oral cavity, and we postulate that the interaction may cause agglutination and early removal of E. coli, thereby preventing colonization by these organisms of oropharyngeal mucosae and dental tissues.

Authors
Babu, JP; Abraham, SN; Dabbous, MK; Beachey, EH
MLA Citation
Babu, JP, Abraham, SN, Dabbous, MK, and Beachey, EH. "Interaction of a 60-kilodalton D-mannose-containing salivary glycoprotein with type 1 fimbriae of Escherichia coli." Infect Immun 54.1 (October 1986): 104-108.
PMID
2875948
Source
pubmed
Published In
Infection and immunity
Volume
54
Issue
1
Publish Date
1986
Start Page
104
End Page
108

Influence of trimethoprim and sulfamethoxazole on the synthesis, expression, and function of type 1 fimbriae of Escherichia coli.

We investigated the effects of low levels of sulfamethoxazole and trimethoprim on biosynthesis, expression at the cell surface, and hemagglutinating activity of type 1 fimbriae from a urinary tract isolate of Escherichia coli. The mannose-sensitive hemagglutination of E. coli was reduced after growth in either of the antimicrobial agents. Moreover, trimethoprim affected antigenic fimbrial expression at the bacterial cell surface. Fimbrial subunit synthesis, as detected in lysates of solubilized whole bacteria, was inhibited in bacteria grown with one-half the minimum inhibitory concentration (MIC) or trimethoprim. Organisms grown in low doses of trimethoprim and sulfamethoxazole (one-thirty-second the MIC each) together exhibited marked reduction of fimbrial synthesis, expression, and hemagglutinating activity. Neither agent induced any detectable effect when used alone at the same concentrations. These results demonstrate that the synergistic activity of these drugs at concentrations below the MIC influence the synthesis, expression, and adhesive properties of type 1 fimbriae.

Authors
Schifferli, DM; Abraham, SN; Beachey, EH
MLA Citation
Schifferli, DM, Abraham, SN, and Beachey, EH. "Influence of trimethoprim and sulfamethoxazole on the synthesis, expression, and function of type 1 fimbriae of Escherichia coli." J Infect Dis 154.3 (September 1986): 490-496.
PMID
2874179
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
154
Issue
3
Publish Date
1986
Start Page
490
End Page
496

The genetic determinant of adhesive function in type 1 fimbriae of Escherichia coli is distinct from the gene encoding the fimbrial subunit.

The role of type 1 fimbriae in the mannose-sensitive attachment of Escherichia coli to eucaryotic cells was investigated by deletion mutation analysis of a recombinant plasmid, pSH2, carrying the genetic information for the synthesis and expression of functional type 1 fimbriae. A mutant, pUT2002, containing a deletion remote from the structural gene encoding the 17-kilodalton subunit protein of type 1 fimbriae failed to agglutinate guinea pig erythrocytes even though the bacteria expressed fimbriae morphologically and antigenically indistinguishable from those produced by the intact recombinant plasmid. Fimbriae isolated from pUT2002 failed to agglutinate guinea pig erythrocytes, but reacted with a monoclonal antibody specific for quaternary structural determinants of type 1 fimbriae. Moreover, the dissociated fimbrial subunits from this mutant were indistinguishable from normal fimbriae by their migration during electrophoresis in sodium dodecyl sulfate-polyacrylamide gels, by their reactivity with a monoclonal antibody directed against a subunit-specific epitope, and in enzyme-linked immunosorbent assays with monospecific antisera. These results indicate that the adhesive functions in type 1 fimbriae are dependent on a factor(s) encoded by a gene other than those required for synthesis, assembly, and expression of the structural 17-kilodalton subunit.

Authors
Minion, FC; Abraham, SN; Beachey, EH; Goguen, JD
MLA Citation
Minion, FC, Abraham, SN, Beachey, EH, and Goguen, JD. "The genetic determinant of adhesive function in type 1 fimbriae of Escherichia coli is distinct from the gene encoding the fimbrial subunit." J Bacteriol 165.3 (March 1986): 1033-1036.
PMID
2419305
Source
pubmed
Published In
Journal of bacteriology
Volume
165
Issue
3
Publish Date
1986
Start Page
1033
End Page
1036

Protection against Escherichia coli-induced urinary tract infections with hybridoma antibodies directed against type 1 fimbriae or complementary D-mannose receptors.

Hybridoma antibodies directed against quaternary structural epitopes of the type 1 fimbrial adhesin of Escherichia coli or against D-mannose, the sugar determinant in the complementary host cell receptor, prevented the attachment of mannose-sensitive E. coli to various eucaryotic cells. Passive intraperitoneal administration of the fimbria-specific or D-mannose-specific antibodies protected mice against retrograde colonization with mannose-sensitive E. coli instilled into their urinary bladders. Monoclonal antibodies directed against fimbrial subunits rather than quaternary structural epitopes or against N-acetylgalactosamine rather than D-mannose residues lacked protective activity. These studies provide evidence that bacterial colonization can be blocked or interrupted by antibodies directed against either the adhesin or the complementary host cell receptor of pathogenic microorganisms.

Authors
Abraham, SN; Babu, JP; Giampapa, CS; Hasty, DL; Simpson, WA; Beachey, EH
MLA Citation
Abraham, SN, Babu, JP, Giampapa, CS, Hasty, DL, Simpson, WA, and Beachey, EH. "Protection against Escherichia coli-induced urinary tract infections with hybridoma antibodies directed against type 1 fimbriae or complementary D-mannose receptors." Infect Immun 48.3 (June 1985): 625-628.
PMID
2860067
Source
pubmed
Published In
Infection and immunity
Volume
48
Issue
3
Publish Date
1985
Start Page
625
End Page
628

Antiadhesive properties of a quaternary structure-specific hybridoma antibody against type 1 fimbriae of Escherichia coli.

The relationship between the structure and biological function of type 1 fimbriae of Escherichia coli was investigated using a set of monoclonal antibodies directed against conformation-specific antigenic determinants. Of three monoclonal antibodies tested, only one (clone CD3) prevented adhesion of the vaccine strain to epithelial cells or guinea pig erythrocytes. The antibody produced by CD3, but not that produced by the other two hybridoma clones (AA8 and GG1), precipitated isolated fimbriae by double diffusion in agar gel and was shown to bind in a highly discrete, periodic manner along the length of each of the fimbriae by immunoelectron microscopy. Immunoelectroblots of type 1 fimbrial subunits and polymers electrophoresed in SDS-gels indicated that the antibodies in AA8 and GG1 reacted only with fimbrial monomers (mol wt 17,000), whereas the antibody in CD3 reacted only with polymers of mol wt 102,000 (hexamers) or higher. ELISA inhibition assays demonstrated that dissociated fimbrial subunits lost their reactivity with antibody CD3 but gained reactivity with antibodies AA8 and GG1. Conversely, when allowed to reassemble in vitro in the presence of 5 mM MgCl2, the reassembled fimbriae lost their reactivity with antibodies AA8 and GG1 but regained reactivity with antibody CD3. These results demonstrated that certain antigenic epitopes are dependent on quaternary structural determinants, whereas others are independent of quaternary fimbrial structure and also are inaccessible for antibody binding in fimbriae once they have been assembled. These monoclonal antibodies should prove useful in studies of the structural determinants of the biological function of type 1 fimbriae as well as in studies of fimbrial synthesis, transport, and assembly.

Authors
Abraham, SN; Hasty, DL; Simpson, WA; Beachey, EH
MLA Citation
Abraham, SN, Hasty, DL, Simpson, WA, and Beachey, EH. "Antiadhesive properties of a quaternary structure-specific hybridoma antibody against type 1 fimbriae of Escherichia coli." J Exp Med 158.4 (October 1, 1983): 1114-1128.
PMID
6194242
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
158
Issue
4
Publish Date
1983
Start Page
1114
End Page
1128

Adherence of streptococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa to fibronectin-coated and uncoated epithelial cells.

The relationship between the variability in the fibronectin (Fn) content on human buccal epithelial cells and the capacity of the cells to bind gram-positive (Streptococcus pyogenes) or gram-negative (Escherichia coli or Pseudomonas aeruginosa) bacteria was investigated. Adhesion experiments performed with mixtures of epithelial cells and mixed suspensions of either S. pyogenes and E. coli or S. pyogenes and P. aeruginosa exhibited three major populations of buccal cells: one of these was able to bind S. pyogenes (gram positive) but neither of the gram-negative bacteria; a second population was able to bind the gram-negative but not the gram-positive bacteria; and a third was able to bind various numbers of both types of organisms. Further adhesion experiments performed with a mixture of epithelial cells and a mixed suspension of S. pyrogens, E. coli, and fluoresceinconjugated methacrylate beads coated with immune immunoglobulin G directed against Fn revealed that the epithelial cells recognizing the gram-positive bacteria were rich in Fn, whereas those recognizing the gram-negative organisms were poor in Fn. Immunoelectron microscopy confirmed that cells of S. pyogenes bound to epithelial cells coated with Fn, whereas cells of E. coli bound to epithelial cells lacking Fn. These results suggest that Fn on the surfaces of epithelial cells may modulate the ecology of the human oropharyngeal cavity, especially with respect to the colonization of these surfaces by pathogenic gram-negative or gram-positive bacteria.

Authors
Abraham, SN; Beachey, EH; Simpson, WA
MLA Citation
Abraham, SN, Beachey, EH, and Simpson, WA. "Adherence of streptococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa to fibronectin-coated and uncoated epithelial cells." Infect Immun 41.3 (September 1983): 1261-1268.
PMID
6411621
Source
pubmed
Published In
Infection and immunity
Volume
41
Issue
3
Publish Date
1983
Start Page
1261
End Page
1268

A comparative study of the mannose-resistant and mannose-sensitive haemagglutinins of Escherichia coli isolated from urinary tract infections.

The distribution of mannose-resistant (MRHA) and mannose-sensitive (MSHA) fimbrial haemagglutinins was examined in 482 strains of Escherichia coli isolated from 390 adult women and 45 pregnant mothers with a variety of urinary tract infections (UTI), and from 47 healthy controls. The proportion of MRHA strains was significantly higher in patients with symptomatic UTI (75%) than in women with non-significant bacteriuria (30%, p less than 0.001), pregnant women with asymptomatic UTI (34%, p less than 0.0001) and healthy controls (0%). The proportion of MSHA strains was significantly lower in patients with symptomatic UTI (22%) than in women with non-significant bacteriuria (46%, p less than 0.001) and pregnant women with asymptomatic UTI (52%, p less than 0.01). Only 17% of the strains from healthy controls had MSHA activity. In pregnant women with UTI, whether this was symptomatic or asymptomatic, there was a significant association between infection with MRHA strains of E. coli and a past history of UTI. Thus, in a pregnant woman with an infection and a past history of UTI there is a seven-fold greater chance that this infection is due to an MRHA-bearing organism than in pregnant women without such a history. There was also a significant association between MRHA organisms and symptomatic infection. The risk of symptomatic patients having an infection with an MRHA strain is six times greater than that for a patient with a covert infection.

Authors
Parry, SH; Boonchai, S; Abraham, SN; Salter, JM; Rooke, DM; Simpson, JM; Bint, AJ; Sussman, M
MLA Citation
Parry, SH, Boonchai, S, Abraham, SN, Salter, JM, Rooke, DM, Simpson, JM, Bint, AJ, and Sussman, M. "A comparative study of the mannose-resistant and mannose-sensitive haemagglutinins of Escherichia coli isolated from urinary tract infections." Infection 11.2 (March 1983): 123-128.
PMID
6134680
Source
pubmed
Published In
Infection
Volume
11
Issue
2
Publish Date
1983
Start Page
123
End Page
128

Human natural killer cells analyzed by B73.1, a monoclonal antibody blocking Fc receptor functions. I. Characterization of the lymphocyte subset reactive with B73.1

We describe the production of the monoclonal antibody B73.1, reacting with a subset of human lymphocytes and, in about one-half of the donors, with neutrophilic polymorphonuclear leukocytes. In the peripheral blood from normal adult donors, 14.6 ± 8.5% of the lymphocytes react with B73.1 antibody. The B73.1(+) lymphocyte subset does not bear markers of typical T or B cells and corresponds to the lymphocyte subset containing antibody-dependent killer (K) and natural killer (NK) cells. We demonstrate that: a) virtually all lymphocytes with K/NK cytotoxic activity are found in the lymphocyte subpopulation bearing the B73.1-defined antigen; b) the B73.1(+) lymphocyte subset bears the combination of antigens known to be present on K/NK cells; and c) there is a positive correlation between the level of cytotoxicity and the actual number of B73.1(+) lymphocytes in individual donors. We also report the distribution of B73.1(+) lymphocytes according to donor age and tissue types. The use of the B73.1 antibody in quantitating the actual number of K/NK cells and in performing functional studies on spontaneous cytotoxicity is discussed.

Authors
Perussia, B; Starr, S; Abraham, S; Fanning, V; Trinchieri, G
MLA Citation
Perussia, B, Starr, S, Abraham, S, Fanning, V, and Trinchieri, G. "Human natural killer cells analyzed by B73.1, a monoclonal antibody blocking Fc receptor functions. I. Characterization of the lymphocyte subset reactive with B73.1." Journal of Immunology 130.5 (1983): 2133-2141.
PMID
6833758
Source
scival
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
130
Issue
5
Publish Date
1983
Start Page
2133
End Page
2141

Incidence of free-living amoebae in the nasal passages of local population in Zaria, Nigeria.

Following the observation of cases of primary amoebic meningoencephalitis (PAME) during the dusty harmattan period in Zaria, a survey was carried out in randomly selected local populations of Zaria, to find out the incidence of free-living amoebae in the nasal passages. The times of sampling were spaced so as to cover both the rainy (non-harmattan) abd dry (harmattan) seasons. In all 1250 individuals were sampled, and were grouped in the three age groups of above 18 years, between 4 and 18 years and below 4 years. The overall incidence was 4.2% (52 out of 1250). There was no marked difference in the three age groups studied. The incidence rate in males was 4.8% (30 of 630) and that in females was 3.5% (22 of 620). Nine different species of free-living amoebae were isolated. Six belonged to the Genus Hartmannella, two to the genus Naegleria, and one to the genus Schizopyrenus. Three species were found to be pathogenic for mice: H. culbertsoni, H. rhysodes and N. fowleri. It was observed from this study that a significant percentage of the Zaria population carry free-living amoebae in the nasal passages. The monthly incidence rate in population ranged from 1.8 to 3.1% during the rainy (non-harmattan) season whereas in the dry (harmattan) season it ranged from 4.2 to 7.9%. The highest incidence rate coincided with the peak of the dry (harmattan) season. The possible role of harmattan winds on the nasal carriage as well as the necessity to investigate fully the disease PAME in this environment is discussed.

Authors
Abraham, SN; Lawande, RV
MLA Citation
Abraham, SN, and Lawande, RV. "Incidence of free-living amoebae in the nasal passages of local population in Zaria, Nigeria." J Trop Med Hyg 85.5 (October 1982): 217-222.
PMID
7176005
Source
pubmed
Published In
Journal of Tropical Medicine and Hygiene
Volume
85
Issue
5
Publish Date
1982
Start Page
217
End Page
222

Urinary tract infection due to laboratory-acquired Escherichia coli: relation to virulence.

Authors
Parry, SH; Abraham, SN; Feavers, IM; Lee, M; Jones, MR; Bint, AJ; Sussman, M
MLA Citation
Parry, SH, Abraham, SN, Feavers, IM, Lee, M, Jones, MR, Bint, AJ, and Sussman, M. "Urinary tract infection due to laboratory-acquired Escherichia coli: relation to virulence." Br Med J (Clin Res Ed) 282.6268 (March 21, 1981): 949-950.
PMID
6781667
Source
pubmed
Published In
British medical journal (Clinical research ed.)
Volume
282
Issue
6268
Publish Date
1981
Start Page
949
End Page
950

Recovery of soil Amebas from the nasal passages of children during the dusty harmattan period in Zaria.

Following a fatal case of primary amebic meningoencephalitis during the dusty harmattan period in an 8-month-old child in whose case Naegleria fowleri was recovered both from the cerebrospinal fluid and from material from the nose in absence of a history of swimming, it was hypothesized that dust during the harmattan might harbor amebic cysts, which may be inhaled by human beings and cause infection. A preliminary survey was thus carried out to examine the nasal passages of children for the presence of soil amebas during the harmattan. In all, 50 children were evaluated for the presence of soil amebas. Positive cultures for the soil amebas were obtained from 12 children (24%). Four species of amebas were isolated singly or in combination with other species. Pathogenic Naegleria fowleri, proved pathogenic for mice, were cultured from specimens from two children.

Authors
Lawande, RV; Abraham, SN; John, I; Egler, LJ
MLA Citation
Lawande, RV, Abraham, SN, John, I, and Egler, LJ. "Recovery of soil Amebas from the nasal passages of children during the dusty harmattan period in Zaria." Am J Clin Pathol 71.2 (February 1979): 201-203.
PMID
425935
Source
pubmed
Published In
American Journal of Clinical Pathology
Volume
71
Issue
2
Publish Date
1979
Start Page
201
End Page
203

c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice.

RATIONALE: Previously, we demonstrated a candidate region for susceptibility to airspace enlargement on mouse chromosome 5. However, the specific candidate genes within this region accounting for emphysema-like changes remain unrecognized. c-Kit is a receptor tyrosine kinase within this candidate gene region that has previously been recognized to contribute to the survival, proliferation, and differentiation of hematopoietic stem cells. Increases in the percentage of cells expressing c-Kit have previously been associated with protection against injury-induced emphysema. OBJECTIVES: Determine whether genetic variants of c-Kit are associated with spontaneous airspace enlargement. METHODS: Perform single-nucleotide polymorphism association studies in the mouse strains at the extremes of airspace enlargement phenotype for variants in c-Kit tyrosine kinase. Characterize mice bearing functional variants of c-Kit compared with wild-type controls for the development of spontaneous airspace enlargement. Epithelial cell proliferation was measured in culture. MEASUREMENTS AND MAIN RESULTS: Upstream regulatory single-nucleotide polymorphisms in the divergent mouse strains were associated with the lung compliance difference observed between the extreme strains. c-Kit mutant mice (Kit(W-sh)/(W-sh)), when compared with genetic controls, developed altered lung histology, increased total lung capacity, increased residual volume, and increased lung compliance that persist into adulthood. c-Kit inhibition with imatinib attenuated in vitro proliferation of cells expressing epithelial cell adhesion molecule. CONCLUSIONS: Our findings indicate that c-Kit sustains and/or maintains normal alveolar architecture in the lungs of mice. In vitro data suggest that c-Kit can regulate epithelial cell clonal expansion. The precise mechanisms that c-Kit contributes to the development of airspace enlargement and increased lung compliance remain unclear and warrants further investigation.

Authors
Lindsey, JY; Ganguly, K; Brass, DM; Li, Z; Potts, EN; Degan, S; Chen, H; Brockway, B; Abraham, SN; Berndt, A; Stripp, BR; Foster, WM; Leikauf, GD; Schulz, H; Hollingsworth, JW
MLA Citation
Lindsey, JY, Ganguly, K, Brass, DM, Li, Z, Potts, EN, Degan, S, Chen, H, Brockway, B, Abraham, SN, Berndt, A, Stripp, BR, Foster, WM, Leikauf, GD, Schulz, H, and Hollingsworth, JW. "c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice." Am J Respir Crit Care Med 183.12: 1644-1652.
PMID
21471107
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
183
Issue
12
Start Page
1644
End Page
1652
DOI
10.1164/rccm.201007-1157OC

Barriers to preclinical investigations of anti-dengue immunity and dengue pathogenesis.

Dengue virus (DENV) is a human pathogen that causes severe and potentially fatal disease in millions of individuals each year. Immune-mediated pathology is thought to underlie many of the complications of DENV infection in humans, but the notable limitations of the available animal models have impeded our knowledge of the interactions between DENV and the immune system. In this Opinion article, we discuss some of the controversies in the field of dengue research relating to the interaction between DENV and the mammalian host. We highlight key barriers hindering our understanding of the molecular pathogenesis of DENV and offer suggestions for the most effective ways in which the role of the immune system in the protection from, and pathology of, DENV infection can be addressed experimentally.

Authors
St John, AL; Abraham, SN; Gubler, DJ
MLA Citation
St John, AL, Abraham, SN, and Gubler, DJ. "Barriers to preclinical investigations of anti-dengue immunity and dengue pathogenesis." Nat Rev Microbiol 11.6: 420-426. (Review)
PMID
23652323
Source
pubmed
Published In
Nature Reviews Microbiology
Volume
11
Issue
6
Start Page
420
End Page
426
DOI
10.1038/nrmicro3030
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