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Horner, Stacy M.

Positions:

Assistant Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2007

Ph.D. — Yale University

News:

Grants:

Defining the role of the RNA modification N6-methyladenosine in the hepatitis C virus lifecycle

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 01, 2016
End Date
May 31, 2021

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

Amelioration of neural stem cell defects underlying Zika virus induced microcephaly

Administered By
Molecular Genetics and Microbiology
AwardedBy
Hartwell Foundation
Role
Collaborator
Start Date
April 01, 2017
End Date
March 31, 2020

Zika virus infection of neural stem cells to model pathogen-induced microcephaly

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 2016
End Date
August 31, 2018

Defining novel Riplet-activated antiviral innate immune signaling pathways

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 08, 2016
End Date
June 30, 2018

Innate Immune Regulation during hepatitis C virus infection

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
December 15, 2013
End Date
November 30, 2015
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Publications:

RNA modifications go viral.

Authors
Gokhale, NS; Horner, SM
MLA Citation
Gokhale, NS, and Horner, SM. "RNA modifications go viral." PLoS pathogens 13.3 (March 9, 2017): e1006188-.
PMID
28278189
Source
epmc
Published In
PLoS pathogens
Volume
13
Issue
3
Publish Date
2017
Start Page
e1006188
DOI
10.1371/journal.ppat.1006188

Protect this house: cytosolic sensing of viruses.

The ability to recognize invading viral pathogens and to distinguish their components from those of the host cell is critical to initiate the innate immune response. The efficiency of this detection is an important factor in determining the susceptibility of the cell to viral infection. Innate sensing of viruses is, therefore, an indispensable step in the line of defense for cells and organisms. Recent discoveries have uncovered novel sensors of viral components and hallmarks of infection, as well as mechanisms by which cells discriminate between self and non-self. This review highlights the mechanisms used by cells to detect viral pathogens in the cytosol, and recent advances in the field of cytosolic sensing of viruses.

Authors
McFadden, MJ; Gokhale, NS; Horner, SM
MLA Citation
McFadden, MJ, Gokhale, NS, and Horner, SM. "Protect this house: cytosolic sensing of viruses." Current opinion in virology 22 (February 2017): 36-43.
PMID
27951430
Source
epmc
Published In
Current Opinion in Virology
Volume
22
Publish Date
2017
Start Page
36
End Page
43
DOI
10.1016/j.coviro.2016.11.012

Knotty Zika Virus Blocks Exonuclease to Produce Subgenomic Flaviviral RNAs.

In a recent issue of Science, Akiyama et al. (2016) prove the existence of a pseudoknot that stabilizes a nuclease-resistant RNA structure in the 3' untranslated region of Zika virus. This reinforced structure blocks the 5'→3' exonuclease Xrn1 for the production of pathogenic subgenomic flaviviral RNAs.

Authors
Gokhale, NS; Horner, SM
MLA Citation
Gokhale, NS, and Horner, SM. "Knotty Zika Virus Blocks Exonuclease to Produce Subgenomic Flaviviral RNAs." Cell host & microbe 21.1 (January 2017): 1-2.
PMID
28081439
Source
epmc
Published In
Cell Host & Microbe
Volume
21
Issue
1
Publish Date
2017
Start Page
1
End Page
2
DOI
10.1016/j.chom.2016.12.013

Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling.

Hepatitis C virus (HCV) infects 200 million people globally, and 60-80% of cases persist as a chronic infection that will progress to cirrhosis and liver cancer in 2-10% of patients. We recently demonstrated that HCV induces aberrant expression of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, encoded by myosin genes in infected hepatocytes. These miRNAs, along with AU-rich-element-mediated decay, suppress IFNL2 and IFNL3, members of the type III interferon (IFN) gene family, to support viral persistence. In this study, we show that miR-208b and miR-499a-5p also dampen type I IFN signaling in HCV-infected hepatocytes by directly down-regulating expression of the type I IFN receptor chain, IFNAR1. Inhibition of these miRNAs by using miRNA inhibitors during HCV infection increased expression of IFNAR1. Additionally, inhibition rescued the antiviral response to exogenous type I IFN, as measured by a marked increase in IFN-stimulated genes and a decrease in HCV load. Treatment of HCV-infected hepatocytes with type I IFN increased expression of myosins over HCV infection alone. Since these miRNAs can suppress type III IFN family members, these data collectively define a novel cross-regulation between type I and III IFNs during HCV infection.

Authors
Jarret, A; McFarland, AP; Horner, SM; Kell, A; Schwerk, J; Hong, M; Badil, S; Joslyn, RC; Baker, DP; Carrington, M; Hagedorn, CH; Gale, M; Savan, R
MLA Citation
Jarret, A, McFarland, AP, Horner, SM, Kell, A, Schwerk, J, Hong, M, Badil, S, Joslyn, RC, Baker, DP, Carrington, M, Hagedorn, CH, Gale, M, and Savan, R. "Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling." Nature medicine 22.12 (December 2016): 1475-1481.
PMID
27841874
Source
epmc
Published In
Nature Medicine
Volume
22
Issue
12
Publish Date
2016
Start Page
1475
End Page
1481
DOI
10.1038/nm.4211

N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection.

The RNA modification N6-methyladenosine (m6A) post-transcriptionally regulates RNA function. The cellular machinery that controls m6A includes methyltransferases and demethylases that add or remove this modification, as well as m6A-binding YTHDF proteins that promote the translation or degradation of m6A-modified mRNA. We demonstrate that m6A modulates infection by hepatitis C virus (HCV). Depletion of m6A methyltransferases or an m6A demethylase, respectively, increases or decreases infectious HCV particle production. During HCV infection, YTHDF proteins relocalize to lipid droplets, sites of viral assembly, and their depletion increases infectious viral particles. We further mapped m6A sites across the HCV genome and determined that inactivating m6A in one viral genomic region increases viral titer without affecting RNA replication. Additional mapping of m6A on the RNA genomes of other Flaviviridae, including dengue, Zika, yellow fever, and West Nile virus, identifies conserved regions modified by m6A. Altogether, this work identifies m6A as a conserved regulatory mark across Flaviviridae genomes.

Authors
Gokhale, NS; McIntyre, ABR; McFadden, MJ; Roder, AE; Kennedy, EM; Gandara, JA; Hopcraft, SE; Quicke, KM; Vazquez, C; Willer, J; Ilkayeva, OR; Law, BA; Holley, CL; Garcia-Blanco, MA; Evans, MJ; Suthar, MS; Bradrick, SS; Mason, CE; Horner, SM
MLA Citation
Gokhale, NS, McIntyre, ABR, McFadden, MJ, Roder, AE, Kennedy, EM, Gandara, JA, Hopcraft, SE, Quicke, KM, Vazquez, C, Willer, J, Ilkayeva, OR, Law, BA, Holley, CL, Garcia-Blanco, MA, Evans, MJ, Suthar, MS, Bradrick, SS, Mason, CE, and Horner, SM. "N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection." Cell host & microbe 20.5 (November 2016): 654-665.
PMID
27773535
Source
epmc
Published In
Cell Host & Microbe
Volume
20
Issue
5
Publish Date
2016
Start Page
654
End Page
665
DOI
10.1016/j.chom.2016.09.015

Innate immune evasion strategies of DNA and RNA viruses.

Upon infection, both DNA and RNA viruses can be sensed by pattern recognition receptors (PRRs) in the cytoplasm or the nucleus to activate antiviral innate immunity. Sensing of viral products leads to the activation of a signaling cascade that ultimately results in transcriptional activation of type I and III interferons, as well as other antiviral genes that together mediate viral clearance and inhibit viral spread. Therefore, in order for viruses to replicate and spread efficiently, they must inhibit the host signaling pathways that induce the innate antiviral immune response. In this review, we will highlight recent advances in the understanding of the mechanisms by which viruses evade PRR detection, intermediate signaling molecule activation, transcription factor activation, and the actions of antiviral proteins.

Authors
Beachboard, DC; Horner, SM
MLA Citation
Beachboard, DC, and Horner, SM. "Innate immune evasion strategies of DNA and RNA viruses." Current opinion in microbiology 32 (August 2016): 113-119.
PMID
27288760
Source
epmc
Published In
Current Opinion in Microbiology
Volume
32
Publish Date
2016
Start Page
113
End Page
119
DOI
10.1016/j.mib.2016.05.015

Posttranscriptional m(6)A Editing of HIV-1 mRNAs Enhances Viral Gene Expression.

Covalent addition of a methyl group to adenosine N(6) (m(6)A) is an evolutionarily conserved and common RNA modification that is thought to modulate several aspects of RNA metabolism. While the presence of multiple m(6)A editing sites on diverse viral RNAs was reported starting almost 40 years ago, how m(6)A editing affects virus replication has remained unclear. Here, we used photo-crosslinking-assisted m(6)A sequencing techniques to precisely map several m(6)A editing sites on the HIV-1 genome and report that they cluster in the HIV-1 3' untranslated region (3' UTR). Viral 3' UTR m(6)A sites or analogous cellular m(6)A sites strongly enhanced mRNA expression in cis by recruiting the cellular YTHDF m(6)A "reader" proteins. Reducing YTHDF expression inhibited, while YTHDF overexpression enhanced, HIV-1 protein and RNA expression, and virus replication in CD4+ T cells. These data identify m(6)A editing and the resultant recruitment of YTHDF proteins as major positive regulators of HIV-1 mRNA expression.

Authors
Kennedy, EM; Bogerd, HP; Kornepati, AVR; Kang, D; Ghoshal, D; Marshall, JB; Poling, BC; Tsai, K; Gokhale, NS; Horner, SM; Cullen, BR
MLA Citation
Kennedy, EM, Bogerd, HP, Kornepati, AVR, Kang, D, Ghoshal, D, Marshall, JB, Poling, BC, Tsai, K, Gokhale, NS, Horner, SM, and Cullen, BR. "Posttranscriptional m(6)A Editing of HIV-1 mRNAs Enhances Viral Gene Expression." Cell host & microbe 19.5 (May 2016): 675-685.
PMID
27117054
Source
epmc
Published In
Cell Host & Microbe
Volume
19
Issue
5
Publish Date
2016
Start Page
675
End Page
685
DOI
10.1016/j.chom.2016.04.002

Cooperation between the Hepatitis C Virus p7 and NS5B Proteins Enhances Virion Infectivity.

The molecular mechanisms that govern hepatitis C virus (HCV) assembly, release, and infectivity are still not yet fully understood. In the present study, we sequenced a genotype 2A strain of HCV (JFH-1) that had been cell culture adapted in Huh-7.5 cells to produce nearly 100-fold-higher viral titers than the parental strain. Sequence analysis identified nine mutations in the genome, present within both the structural and nonstructural genes. The infectious clone of this virus containing all nine culture-adapted mutations had 10-fold-higher levels of RNA replication and RNA release into the supernatant but had nearly 1,000-fold-higher viral titers, resulting in an increased specific infectivity compared to wild-type JFH-1. Two mutations, identified in the p7 polypeptide and NS5B RNA-dependent RNA polymerase, were sufficient to increase the specific infectivity of JFH-1. We found that the culture-adapted mutation in p7 promoted an increase in the size of cellular lipid droplets following transfection of viral RNA. In addition, we found that the culture-adaptive mutations in p7 and NS5B acted synergistically to enhance the specific viral infectivity of JFH-1 by decreasing the level of sphingomyelin in the virion. Overall, these results reveal a genetic interaction between p7 and NS5B that contributes to virion specific infectivity. Furthermore, our results demonstrate a novel role for the RNA-dependent RNA polymerase NS5B in HCV assembly.Hepatitis C virus assembly and release depend on viral interactions with host lipid metabolic pathways. Here, we demonstrate that the viral p7 and NS5B proteins cooperate to promote virion infectivity by decreasing sphingomyelin content in the virion. Our data uncover a new role for the viral RNA-dependent RNA polymerase NS5B and p7 proteins in contributing to virion morphogenesis. Overall, these findings are significant because they reveal a genetic interaction between p7 and NS5B, as well as an interaction with sphingomyelin that regulates virion infectivity. Our data provide new strategies for targeting host lipid-virus interactions as potential targets for therapies against HCV infection.

Authors
Aligeti, M; Roder, A; Horner, SM
MLA Citation
Aligeti, M, Roder, A, and Horner, SM. "Cooperation between the Hepatitis C Virus p7 and NS5B Proteins Enhances Virion Infectivity." Journal of virology 89.22 (November 2015): 11523-11533.
PMID
26355084
Source
epmc
Published In
Journal of virology
Volume
89
Issue
22
Publish Date
2015
Start Page
11523
End Page
11533
DOI
10.1128/jvi.01185-15

Insights into antiviral innate immunity revealed by studying hepatitis C virus.

Experimental studies on the interactions of the positive strand RNA virus hepatitis C virus (HCV) with the host have contributed to several discoveries in the field of antiviral innate immunity. These include revealing the antiviral sensing pathways that lead to the induction of type I interferon (IFN) during HCV infection and also the importance of type III IFNs in the antiviral immune response to HCV. These studies on HCV/host interactions have contributed to our overall understanding of viral sensing and viral evasion of the antiviral intracellular innate immune response. In this review, I will highlight how these studies of HCV/host interactions have led to new insights into antiviral innate immunity. Overall, I hope to emphasize that studying antiviral immunity in the context of virus infection is necessary to fully understand antiviral immunity and how it controls the outcome of viral infection.

Authors
Horner, SM
MLA Citation
Horner, SM. "Insights into antiviral innate immunity revealed by studying hepatitis C virus." Cytokine 74.2 (August 2015): 190-197. (Review)
PMID
25819428
Source
epmc
Published In
Cytokine
Volume
74
Issue
2
Publish Date
2015
Start Page
190
End Page
197
DOI
10.1016/j.cyto.2015.03.007

MAVS Coordination of Antiviral Innate Immunity.

RNA virus infection is sensed in the cytoplasm by the retinoic acid-inducible gene I (RIG-I)-like receptors. These proteins signal through the host adaptor protein MAVS to trigger the antiviral innate immune response. Here, we describe how MAVS subcellular localization impacts its function and the regulation underlying MAVS signaling. We propose a model to describe how the coordination of MAVS functions at the interface between the mitochondria and the mitochondrion-associated endoplasmic reticulum (ER) membrane programs antiviral signaling.

Authors
Vazquez, C; Horner, SM
MLA Citation
Vazquez, C, and Horner, SM. "MAVS Coordination of Antiviral Innate Immunity." Journal of virology 89.14 (July 2015): 6974-6977. (Review)
PMID
25948741
Source
epmc
Published In
Journal of virology
Volume
89
Issue
14
Publish Date
2015
Start Page
6974
End Page
6977
DOI
10.1128/jvi.01918-14

Successes and Challenges on the Road to Cure Hepatitis C.

Authors
Horner, SM; Naggie, S
MLA Citation
Horner, SM, and Naggie, S. "Successes and Challenges on the Road to Cure Hepatitis C." PLoS pathogens 11.6 (June 18, 2015): e1004854-. (Review)
Website
http://hdl.handle.net/10161/10588
PMID
26087286
Source
epmc
Published In
PLoS pathogens
Volume
11
Issue
6
Publish Date
2015
Start Page
e1004854
DOI
10.1371/journal.ppat.1004854

Correction: Proteomic Analysis of Mitochondrial-Associated ER Membranes (MAM) during RNA Virus Infection Reveals Dynamic Changes in Protein and Organelle Trafficking

MLA Citation
"Correction: Proteomic Analysis of Mitochondrial-Associated ER Membranes (MAM) during RNA Virus Infection Reveals Dynamic Changes in Protein and Organelle Trafficking." PLOS ONE 10.4 (April 13, 2015): e0124226-e0124226.
Source
crossref
Published In
PloS one
Volume
10
Issue
4
Publish Date
2015
Start Page
e0124226
End Page
e0124226
DOI
10.1371/journal.pone.0124226

Proteomic analysis of mitochondrial-associated ER membranes (MAM) during RNA virus infection reveals dynamic changes in protein and organelle trafficking.

RIG-I pathway signaling of innate immunity against RNA virus infection is organized between the ER and mitochondria on a subdomain of the ER called the mitochondrial-associated ER membrane (MAM). The RIG-I adaptor protein MAVS transmits downstream signaling of antiviral immunity, with signaling complexes assembling on the MAM in association with mitochondria and peroxisomes. To identify components that regulate MAVS signalosome assembly on the MAM, we characterized the proteome of MAM, ER, and cytosol from cells infected with either chronic (hepatitis C) or acute (Sendai) RNA virus infections, as well as mock-infected cells. Comparative analysis of protein trafficking dynamics during both chronic and acute viral infection reveals differential protein profiles in the MAM during RIG-I pathway activation. We identified proteins and biochemical pathways recruited into and out of the MAM in both chronic and acute RNA viral infections, representing proteins that drive immunity and/or regulate viral replication. In addition, by using this comparative proteomics approach, we identified 3 new MAVS-interacting proteins, RAB1B, VTN, and LONP1, and defined LONP1 as a positive regulator of the RIG-I pathway. Our proteomic analysis also reveals a dynamic cross-talk between subcellular compartments during both acute and chronic RNA virus infection, and demonstrates the importance of the MAM as a central platform that coordinates innate immune signaling to initiate immunity against RNA virus infection.

Authors
Horner, SM; Wilkins, C; Badil, S; Iskarpatyoti, J; Gale, M
MLA Citation
Horner, SM, Wilkins, C, Badil, S, Iskarpatyoti, J, and Gale, M. "Proteomic analysis of mitochondrial-associated ER membranes (MAM) during RNA virus infection reveals dynamic changes in protein and organelle trafficking." PloS one 10.3 (January 2015): e0117963-.
PMID
25734423
Source
epmc
Published In
PloS one
Volume
10
Issue
3
Publish Date
2015
Start Page
e0117963
DOI
10.1371/journal.pone.0117963

Defining the spatial relationship between hepatitis C virus infection and interferon-stimulated gene induction in the human liver.

Authors
Horner, SM
MLA Citation
Horner, SM. "Defining the spatial relationship between hepatitis C virus infection and interferon-stimulated gene induction in the human liver." Hepatology 59.6 (June 2014): 2065-2067.
PMID
24375835
Source
pubmed
Published In
Hepatology
Volume
59
Issue
6
Publish Date
2014
Start Page
2065
End Page
2067
DOI
10.1002/hep.26960

Activation and evasion of antiviral innate immunity by hepatitis c virus

Hepatitis C virus (HCV) chronically infects 130-170 million people worldwide and is a major public health burden. HCV is an RNA virus that infects hepatocytes within liver, and this infection is sensed as non-self by the intracellular innate immune response to program antiviral immunity to HCV. HCV encodes several strategies to evade this antiviral response, and this evasion of innate immunity plays a key role in determining viral persistence. This review discusses the molecular mechanisms of how the intracellular innate immune system detects HCV infection, including how HCV pathogen-associated molecular patterns are generated during infection and where they are recognized as foreign by the innate immune system. Further, this review highlights the key innate immune evasion strategies used by HCV to establish persistent infection within the liver, as well as how host genotype influences the outcome of HCV infection. Understanding these HCV-host interactions is key in understanding how to target HCV during infection and for the design of more effective HCV therapies at the immunological level. © 2013 Elsevier Ltd.

Authors
Horner, SM
MLA Citation
Horner, SM. "Activation and evasion of antiviral innate immunity by hepatitis c virus." Journal of Molecular Biology 426.6 (March 20, 2014): 1198-1209. (Review)
Source
scopus
Published In
Journal of Molecular Biology
Volume
426
Issue
6
Publish Date
2014
Start Page
1198
End Page
1209
DOI
10.1016/j.jmb.2013.10.032

Activation and evasion of antiviral innate immunity by hepatitis C virus.

Hepatitis C virus (HCV) chronically infects 130-170 million people worldwide and is a major public health burden. HCV is an RNA virus that infects hepatocytes within liver, and this infection is sensed as non-self by the intracellular innate immune response to program antiviral immunity to HCV. HCV encodes several strategies to evade this antiviral response, and this evasion of innate immunity plays a key role in determining viral persistence. This review discusses the molecular mechanisms of how the intracellular innate immune system detects HCV infection, including how HCV pathogen-associated molecular patterns are generated during infection and where they are recognized as foreign by the innate immune system. Further, this review highlights the key innate immune evasion strategies used by HCV to establish persistent infection within the liver, as well as how host genotype influences the outcome of HCV infection. Understanding these HCV-host interactions is key in understanding how to target HCV during infection and for the design of more effective HCV therapies at the immunological level.

Authors
Horner, SM
MLA Citation
Horner, SM. "Activation and evasion of antiviral innate immunity by hepatitis C virus." J Mol Biol 426.6 (March 20, 2014): 1198-1209. (Review)
PMID
24184198
Source
pubmed
Published In
Journal of Molecular Biology
Volume
426
Issue
6
Publish Date
2014
Start Page
1198
End Page
1209
DOI
10.1016/j.jmb.2013.10.032

The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs

IFNL3, which encodes interferon-λ3 (IFN-λ3), has received considerable attention in the hepatitis C virus (HCV) field, as many independent genome-wide association studies have identified a strong association between polymorphisms near IFNL3 and clearance of HCV. However, the mechanism underlying this association has remained elusive. In this study, we report the identification of a functional polymorphism (rs4803217) in the 3' untranslated region (UTR) of IFNL3 mRNA that dictated transcript stability. We found that this polymorphism influenced AU-rich element (ARE)-mediated decay (AMD) of IFNL3 mRNA, as well as the binding of HCV-induced microRNAs during infection. Together these pathways mediated robust repression of the unfavorable IFNL3 polymorphism. Our data reveal a previously unknown mechanism by which HCV attenuates the antiviral response and indicate new potential therapeutic targets for HCV treatment.

Authors
McFarland, AP; Horner, SM; Jarret, A; Joslyn, RC; Bindewald, E; Shapiro, BA; Delker, DA; Hagedorn, CH; Carrington, M; Gale, M; Savan, R
MLA Citation
McFarland, AP, Horner, SM, Jarret, A, Joslyn, RC, Bindewald, E, Shapiro, BA, Delker, DA, Hagedorn, CH, Carrington, M, Gale, M, and Savan, R. "The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs." Nature Immunology 15.1 (January 1, 2014): 72-79.
Source
scopus
Published In
Nature Immunology
Volume
15
Issue
1
Publish Date
2014
Start Page
72
End Page
79
DOI
10.1038/ni.2758

Defining the spatial relationship between hepatitis C virus infection and interferon-stimulated gene induction in the human liver

Authors
Horner, SM
MLA Citation
Horner, SM. "Defining the spatial relationship between hepatitis C virus infection and interferon-stimulated gene induction in the human liver." Hepatology 59.6 (January 1, 2014): 2065-2067.
Source
scopus
Published In
Hepatology
Volume
59
Issue
6
Publish Date
2014
Start Page
2065
End Page
2067
DOI
10.1002/hep.26960

Hepatitis C Virus. Strategies to Evade Antiviral Responses.

Hepatitis C virus (HCV) causes chronic liver disease and poses a major clinical and economic burden worldwide. HCV is an RNA virus that is sensed as non-self in the infected liver by host pattern recognition receptors, triggering downstream signaling to interferons (IFNs). The type III IFNs play an important role in immunity to HCV, and human genetic variation in their gene loci is associated with differential HCV infection outcomes. HCV evades host antiviral innate immune responses to mediate a persistent infection in the liver. This review focuses on anti-HCV innate immune sensing, innate signaling and effectors, and the processes and proteins used by HCV to evade and regulate host innate immunity.

Authors
Gokhale, NS; Vazquez, C; Horner, SM
MLA Citation
Gokhale, NS, Vazquez, C, and Horner, SM. "Hepatitis C Virus. Strategies to Evade Antiviral Responses." Future virology 9.12 (January 2014): 1061-1075.
PMID
25983854
Source
epmc
Published In
Future virology
Volume
9
Issue
12
Publish Date
2014
Start Page
1061
End Page
1075
DOI
10.2217/fvl.14.89

Activation and evasion of antiviral innate immunity by hepatitis c virus

Authors
Horner, SM
MLA Citation
Horner, SM. "Activation and evasion of antiviral innate immunity by hepatitis c virus." Journal of Molecular Biology 426.6 (2014): 1198-1209.
Source
scopus
Published In
Journal of Molecular Biology
Volume
426
Issue
6
Publish Date
2014
Start Page
1198
End Page
1209

Regulation of hepatic innate immunity by hepatitis C virus.

Hepatitis C virus (HCV) is a global public health problem involving chronic infection of the liver, which can cause liver disease and is linked with liver cancer. Viral innate immune evasion strategies and human genetic determinants underlie the transition of acute HCV infection to viral persistence and the support of chronic infection. Host genetic factors, such as sequence polymorphisms in IFNL3, a gene in the host interferon system, can influence both the outcome of the infection and the response to antiviral therapy. Recent insights into how HCV regulates innate immune signaling within the liver reveal a complex interaction of patient genetic background with viral and host factors of innate immune triggering and control that imparts the outcome of HCV infection and immunity.

Authors
Horner, SM; Gale, M
MLA Citation
Horner, SM, and Gale, M. "Regulation of hepatic innate immunity by hepatitis C virus." Nature medicine 19.7 (July 2013): 879-888. (Review)
PMID
23836238
Source
epmc
Published In
Nature Medicine
Volume
19
Issue
7
Publish Date
2013
Start Page
879
End Page
888
DOI
10.1038/nm.3253

The mitochondrial targeting chaperone 14-3-3ε regulates a RIG-I translocon that mediates membrane association and innate antiviral immunity.

RIG-I is a cytosolic pathogen recognition receptor that initiates immune responses against RNA viruses. Upon viral RNA recognition, antiviral signaling requires RIG-I redistribution from the cytosol to membranes where it binds the adaptor protein, MAVS. Here we identify the mitochondrial targeting chaperone protein, 14-3-3ε, as a RIG-I-binding partner and essential component of a translocation complex or "translocon" containing RIG-I, 14-3-3ε, and the TRIM25 ubiquitin ligase. The RIG-I translocon directs RIG-I redistribution from the cytosol to membranes where it mediates MAVS-dependent innate immune signaling during acute RNA virus infection. 14-3-3ε is essential for the stable interaction of RIG-I with TRIM25, which facilitates RIG-I ubiquitination and initiation of innate immunity against hepatitis C virus and other pathogenic RNA viruses. Our results define 14-3-3ε as a key component of a RIG-I translocon required for innate antiviral immunity.

Authors
Liu, HM; Loo, Y-M; Horner, SM; Zornetzer, GA; Katze, MG; Gale, M
MLA Citation
Liu, HM, Loo, Y-M, Horner, SM, Zornetzer, GA, Katze, MG, and Gale, M. "The mitochondrial targeting chaperone 14-3-3ε regulates a RIG-I translocon that mediates membrane association and innate antiviral immunity." Cell host & microbe 11.5 (May 2012): 528-537.
PMID
22607805
Source
epmc
Published In
Cell Host & Microbe
Volume
11
Issue
5
Publish Date
2012
Start Page
528
End Page
537
DOI
10.1016/j.chom.2012.04.006

Control of innate immune signaling and membrane targeting by the Hepatitis C virus NS3/4A protease are governed by the NS3 helix α0.

Hepatitis C virus (HCV) infection is sensed in the host cell by the cytosolic pathogen recognition receptor RIG-I. RIG-I signaling is propagated through its signaling adaptor protein MAVS to drive activation of innate immunity. However, HCV blocks RIG-I signaling through viral NS3/4A protease cleavage of MAVS on the mitochondrion-associated endoplasmic reticulum (ER) membrane (MAM). The multifunctional HCV NS3/4A serine protease is associated with intracellular membranes, including the MAM, through membrane-targeting domains within NS4A and also at the amphipathic helix α(0) of NS3. The serine protease domain of NS3 is required for both cleavage of MAVS, a tail-anchored membrane protein, and processing the HCV polyprotein. Here, we show that hydrophobic amino acids in the NS3 helix α(0) are required for selective cleavage of membrane-anchored portions of the HCV polyprotein and for cleavage of MAVS for control of RIG-I pathway signaling of innate immunity. Further, we found that the hydrophobic composition of NS3 helix α(0) is essential to establish HCV replication and infection. Alanine substitution of individual hydrophobic amino acids in the NS3 helix α(0) impaired HCV RNA replication in cells with a functional RIG-I pathway, but viral RNA replication was rescued in cells lacking RIG-I signaling. Therefore, the hydrophobic amphipathic helix α(0) of NS3 is required for NS3/4A control of RIG-I signaling and HCV replication by directing the membrane targeting of both viral and cellular substrates.

Authors
Horner, SM; Park, HS; Gale, M
MLA Citation
Horner, SM, Park, HS, and Gale, M. "Control of innate immune signaling and membrane targeting by the Hepatitis C virus NS3/4A protease are governed by the NS3 helix α0." Journal of virology 86.6 (March 2012): 3112-3120.
PMID
22238314
Source
epmc
Published In
Journal of virology
Volume
86
Issue
6
Publish Date
2012
Start Page
3112
End Page
3120
DOI
10.1128/jvi.06727-11

Regulation of innate immunity and interferon defenses by hepatitis C virus

Authors
Horner, SM; Gale, M
MLA Citation
Horner, SM, and Gale, M. "Regulation of innate immunity and interferon defenses by hepatitis C virus." Chronic Hepatitis B and C: Basic Science to Clinical Applications. January 1, 2012. 245-269.
Source
scopus
Publish Date
2012
Start Page
245
End Page
269
DOI
10.1142/9789814299794_0009

Convergent evolution of escape from hepaciviral antagonism in primates.

The ability to mount an interferon response on sensing viral infection is a critical component of mammalian innate immunity. Several viruses directly antagonize viral sensing pathways to block activation of the host immune response. Here, we show that recurrent viral antagonism has shaped the evolution of the host protein MAVS--a crucial component of the viral-sensing pathway in primates. From sequencing and phylogenetic analyses of MAVS from 21 simian primates, we found that MAVS has evolved under strong positive selection. We focused on how this positive selection has shaped MAVS' susceptibility to Hepatitis C virus (HCV). We functionally tested MAVS proteins from diverse primate species for their ability to resist antagonism by HCV, which uses its protease NS3/4A to cleave human MAVS. We found that MAVS from multiple primates are resistant to inhibition by the HCV protease. This resistance maps to single changes within the protease cleavage site in MAVS, which protect MAVS from getting cleaved by the HCV protease. Remarkably, most of these changes have been independently acquired at a single residue 506 that evolved under positive selection. We show that "escape" mutations lower affinity of the NS3 protease for MAVS and allow it to better restrict HCV replication. We further show that NS3 proteases from all other primate hepaciviruses, including the highly divergent GBV-A and GBV-C viruses, are functionally similar to HCV. We conclude that convergent evolution at residue 506 in multiple primates has resulted in escape from antagonism by hepaciviruses. Our study provides a model whereby insights into the ancient history of viral infections in primates can be gained using extant host and virus genes. Our analyses also provide a means by which primates might clear infections by extant hepaciviruses like HCV.

Authors
Patel, MR; Loo, Y-M; Horner, SM; Gale, M; Malik, HS
MLA Citation
Patel, MR, Loo, Y-M, Horner, SM, Gale, M, and Malik, HS. "Convergent evolution of escape from hepaciviral antagonism in primates." PLoS biology 10.3 (January 2012): e1001282-.
PMID
22427742
Source
epmc
Published In
PLoS biology
Volume
10
Issue
3
Publish Date
2012
Start Page
e1001282
DOI
10.1371/journal.pbio.1001282

Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus.

RIG-I is a cytosolic pathogen recognition receptor that engages viral RNA in infected cells to trigger innate immune defenses through its adaptor protein MAVS. MAVS resides on mitochondria and peroxisomes, but how its signaling is coordinated among these organelles has not been defined. Here we show that a major site of MAVS signaling is the mitochondrial-associated membrane (MAM), a distinct membrane compartment that links the endoplasmic reticulum to mitochondria. During RNA virus infection, RIG-I is recruited to the MAM to bind MAVS. Dynamic MAM tethering to mitochondria and peroxisomes then coordinates MAVS localization to form a signaling synapse between membranes. Importantly, the hepatitis C virus NS3/4A protease, which cleaves MAVS to support persistent infection, targets this synapse for MAVS proteolysis from the MAM, but not from mitochondria, to ablate RIG-I signaling of immune defenses. Thus, the MAM mediates an intracellular immune synapse that directs antiviral innate immunity.

Authors
Horner, SM; Liu, HM; Park, HS; Briley, J; Gale, M
MLA Citation
Horner, SM, Liu, HM, Park, HS, Briley, J, and Gale, M. "Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus." Proceedings of the National Academy of Sciences of the United States of America 108.35 (August 15, 2011): 14590-14595.
PMID
21844353
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
35
Publish Date
2011
Start Page
14590
End Page
14595
DOI
10.1073/pnas.1110133108

Intracellular innate immune cascades and interferon defenses that control hepatitis C virus.

Hepatitis C virus (HCV) is a global public health problem that mediates a persistent infection in nearly 200 million people. HCV is efficient in establishing chronicity due in part to the inefficiency of the host immune system in controlling and counteracting HCV-mediated evasion strategies. HCV persistence is linked to the ability of the virus to suppress the RIG-I pathway and interferon production from infected hepatocytes, thus evading innate immune defenses within the infected cell. This review describes the virus and host processes that regulate the RIG-I pathway during HCV infection. An understanding of these HCV-host interactions could lead to more effective therapies for HCV designed to reactivate the host immune response following HCV infection.

Authors
Horner, SM; Gale, M
MLA Citation
Horner, SM, and Gale, M. "Intracellular innate immune cascades and interferon defenses that control hepatitis C virus." Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 29.9 (September 2009): 489-498. (Review)
PMID
19708811
Source
epmc
Published In
Journal of Interferon & Cytokine Research
Volume
29
Issue
9
Publish Date
2009
Start Page
489
End Page
498
DOI
10.1089/jir.2009.0063

The DNA binding domain of a papillomavirus E2 protein programs a chimeric nuclease to cleave integrated human papillomavirus DNA in HeLa cervical carcinoma cells.

Viral DNA binding proteins that direct nucleases or other protein domains to viral DNA in lytically or latently infected cells may provide a novel approach to modulate viral gene expression or replication. Cervical carcinogenesis is initiated by high-risk human papillomavirus (HPV) infection, and viral DNA persists in the cancer cells. To test whether a DNA binding domain of a papillomavirus protein can direct a nuclease domain to cleave HPV DNA in cervical cancer cells, we fused the DNA binding domain of the bovine papillomavirus type 1 (BPV1) E2 protein to the catalytic domain of the FokI restriction endonuclease, generating a BPV1 E2-FokI chimeric nuclease (BEF). BEF introduced DNA double-strand breaks on both sides of an E2 binding site in vitro, whereas DNA binding or catalytic mutants of BEF did not. After expression of BEF in HeLa cervical carcinoma cells, we detected cleavage at E2 binding sites in the integrated HPV18 DNA in these cells and also at an E2 binding site in cellular DNA. BEF-expressing cells underwent senescence, which required the DNA binding activity of BEF, but not its nuclease activity. These results demonstrate that DNA binding domains of viral proteins can target effector molecules to cognate binding sites in virally infected cells.

Authors
Horner, SM; DiMaio, D
MLA Citation
Horner, SM, and DiMaio, D. "The DNA binding domain of a papillomavirus E2 protein programs a chimeric nuclease to cleave integrated human papillomavirus DNA in HeLa cervical carcinoma cells." Journal of virology 81.12 (June 2007): 6254-6264.
PMID
17392356
Source
epmc
Published In
Journal of virology
Volume
81
Issue
12
Publish Date
2007
Start Page
6254
End Page
6264
DOI
10.1128/jvi.00232-07

Repression of the human papillomavirus E6 gene initiates p53-dependent, telomerase-independent senescence and apoptosis in HeLa cervical carcinoma cells.

Cervical cancer cells express high-risk human papillomavirus (HPV) E6 and E7 proteins. When both HPV oncogenes are repressed in HeLa cervical carcinoma cells, the dormant p53 and retinoblastoma (Rb) tumor suppressor pathways are activated, and the cells undergo senescence in the absence of apoptosis. When the E6 gene is repressed in cells that continue to express an E7 gene, the p53 pathway, but not the Rb pathway, is activated, and both senescence and apoptosis are triggered. To determine the role of p53 signaling in senescence or apoptosis after repression of HPV oncogenes, we introduced a dominant-negative allele of p53 into HeLa cells. Dominant-negative p53 prevented senescence and apoptosis when E6 alone was repressed but did not inhibit senescence when both E6 and E7 were repressed. To determine whether reduced telomerase activity was involved in senescence or apoptosis after E6 repression, we generated HeLa cells stably expressing an exogenous hTERT gene, which encodes the catalytic subunit of telomerase. Although these cells contained markedly elevated telomerase activity and elongated telomeres, hTERT expression did not prevent senescence and apoptosis when E6 alone was repressed. These results demonstrate that when the Rb tumor suppressor pathway is inactivated by the E7 protein, E6 repression activates p53 signaling, which in turn is required for growth inhibition, senescence, and apoptosis. Thus, sustained inactivation of the p53 pathway by the E6 protein is required for maintenance of the proliferative phenotype of HeLa cervical carcinoma cells.

Authors
Horner, SM; DeFilippis, RA; Manuelidis, L; DiMaio, D
MLA Citation
Horner, SM, DeFilippis, RA, Manuelidis, L, and DiMaio, D. "Repression of the human papillomavirus E6 gene initiates p53-dependent, telomerase-independent senescence and apoptosis in HeLa cervical carcinoma cells." Journal of virology 78.8 (April 2004): 4063-4073.
PMID
15047823
Source
epmc
Published In
Journal of virology
Volume
78
Issue
8
Publish Date
2004
Start Page
4063
End Page
4073
DOI
10.1128/jvi.78.8.4063-4073.2004

Visualization of retroviral replication in living cells reveals budding into multivesicular bodies.

Retroviral assembly and budding is driven by the Gag polyprotein and requires the host-derived vacuolar protein sorting (vps) machinery. With the exception of human immunodeficiency virus (HIV)-infected macrophages, current models predict that the vps machinery is recruited by Gag to viral budding sites at the cell surface. However, here we demonstrate that HIV Gag and murine leukemia virus (MLV) Gag also drive assembly intracellularly in cell types including 293 and HeLa cells, previously believed to exclusively support budding from the plasma membrane. Using live confocal microscopy in conjunction with electron microscopy of cells generating fluorescently labeled virions or virus-like particles, we observed that these retroviruses utilize late endosomal membranes/multivesicular bodies as assembly sites, implying an endosome-based pathway for viral egress. These data suggest that retroviruses can interact with the vps sorting machinery in a more traditional sense, directly linked to the mechanism by which cellular proteins are sorted into multivesicular endosomes.

Authors
Sherer, NM; Lehmann, MJ; Jimenez-Soto, LF; Ingmundson, A; Horner, SM; Cicchetti, G; Allen, PG; Pypaert, M; Cunningham, JM; Mothes, W
MLA Citation
Sherer, NM, Lehmann, MJ, Jimenez-Soto, LF, Ingmundson, A, Horner, SM, Cicchetti, G, Allen, PG, Pypaert, M, Cunningham, JM, and Mothes, W. "Visualization of retroviral replication in living cells reveals budding into multivesicular bodies." Traffic (Copenhagen, Denmark) 4.11 (November 2003): 785-801.
PMID
14617360
Source
epmc
Published In
Traffic
Volume
4
Issue
11
Publish Date
2003
Start Page
785
End Page
801
DOI
10.1034/j.1600-0854.2003.00135.x

Synthesis of a novel pyrene-containing nucleoside and its incorporation into oligonucleotides

Authors
Frazer, JD; Horner, SM; Woski, SA
MLA Citation
Frazer, JD, Horner, SM, and Woski, SA. "Synthesis of a novel pyrene-containing nucleoside and its incorporation into oligonucleotides." Tetrahedron Letters 39.11 (March 1998): 1279-1282.
Source
crossref
Published In
Tetrahedron Letters
Volume
39
Issue
11
Publish Date
1998
Start Page
1279
End Page
1282
DOI
10.1016/S0040-4039(97)10853-X
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Research Areas:

  • Animals
  • Cell Biology
  • Hepacivirus
  • Hepatitis C
  • Hepatitis C virus
  • Host-Pathogen Interactions
  • Host-virus relationships
  • Immune Evasion
  • Immunity, Innate
  • Interferon
  • Interferons
  • Liver
  • Models, Biological
  • RNA Viruses
  • Signal Transduction