Giuseppe
Emeritus
Distinct Patterns of IFITM-Mediated Restriction of Filoviruses, SARS Coronavirus, and Influenza A Virus (PLoS Pathogens, abstract, edited)
[Source: PLoS Pathogens, full text: <cite cite="http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001258?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+plospathogens%2FNewArticles+%28Ambra+-+Pathogens+New+Articles%29">PLoS Pathogens: Distinct Patterns of IFITM-Mediated Restriction of Filoviruses, SARS Coronavirus, and Influenza A Virus</cite>. Abstract, edited.]
Distinct Patterns of IFITM-Mediated Restriction of Filoviruses, SARS Coronavirus, and Influenza A Virus
l-Chueh Huang 1*, Charles C. Bailey 1, Jessica L. Weyer 1, Sheli R. Radoshitzky 2, Michelle M. Becker 3, Jessica J. Chiang 1, Abraham L. Brass 4, Asim A. Ahmed 5, Xiaoli Chi 2, Lian Dong 2, Lindsay E. Longobardi 2, Dutch Boltz 2, Jens H. Kuhn 6,7, Stephen J. Elledge 8, Sina Bavari 2, Mark R. Denison 3, Hyeryun Choe 5, Michael Farzan 1*
1 Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America,
2 US Army Medical Research Institute of Infectious Disease, National Interagency Biodefense Campus, Frederick, Maryland, United States of America,
3 Departments of Pediatrics and Microbiology and Immunology and Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America,
4 Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard Medical School, Charlestown, Massachusetts, United States of America,
5 Department of Pediatrics, Harvard Medical School, Children's Hospital, Boston, Massachusetts, United States of America,
6 Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Interagency Biodefense Campus, Frederick, Maryland, United States of America,
7 Tunnell Consulting Inc., King of Prussia, Pennsylvania, United States of America,
8 Department of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America
Abstract
Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM1, 2, and 3) are recently identified viral restriction factors that inhibit infection mediated by the influenza A virus (IAV) hemagglutinin (HA) protein. Here we show that IFITM proteins restricted infection mediated by the entry glycoproteins (GP1,2) of Marburg and Ebola filoviruses (MARV, EBOV). Consistent with these observations, interferon-β specifically restricted filovirus and IAV entry processes. IFITM proteins also inhibited replication of infectious MARV and EBOV. We observed distinct patterns of IFITM-mediated restriction: compared with IAV, the entry processes of MARV and EBOV were less restricted by IFITM3, but more restricted by IFITM1. Moreover, murine Ifitm5 and 6 did not restrict IAV, but efficiently inhibited filovirus entry. We further demonstrate that replication of infectious SARS coronavirus (SARS-CoV) and entry mediated by the SARS-CoV spike (S) protein are restricted by IFITM proteins. The profile of IFITM-mediated restriction of SARS-CoV was more similar to that of filoviruses than to IAV. Trypsin treatment of receptor-associated SARS-CoV pseudovirions, which bypasses their dependence on lysosomal cathepsin L, also bypassed IFITM- mediated restriction. However, IFITM proteins did not reduce cellular cathepsin activity or limit access of virions to acidic intracellular compartments. Our data indicate that IFITM-mediated restriction is localized to a late stage in the endocytic pathway. They further show that IFITM proteins differentially restrict the entry of a broad range of enveloped viruses, and modulate cellular tropism independently of viral receptor expression.
Author Summary
Cells express restriction factors, proteins whose primary activity is to inhibit viral replication. We have recently described a family of restriction factors, interferon-inducible transmembrane (IFITM) proteins, that interfere with replication of influenza A virus. The IFITM proteins uniquely inhibit replication early in the viral life-cycle, before the virus can successfully enter the cell cytoplasm. Here we show that the entry processes of several highly pathogenic viruses ? Marburg virus, Ebola virus, and SARS coronavirus ? are similarly disrupted by IFITM proteins. We compared IFITM-mediated restriction of these viruses with influenza A virus, and discovered that individual IFITM proteins are specialized for restriction. For example, we describe two mouse IFITM proteins that efficiently restrict entry of Marburg and Ebola viruses, but which do not inhibit influenza A virus. We further show that we can circumvent IFITM-mediated restriction by inducing a virus to enter a cell at or near the plasma membrane. This observation indicates that restriction is not a global property of the cell, but rather is localized to late endosomal and lysosomal compartments, the usual entry sites of IFITM-restricted viruses. This study therefore enhances our understanding of how the innate immune system controls influenza A virus and other pathogenic viruses.
Citation: Huang I-C, Bailey CC, Weyer JL, Radoshitzky SR, Becker MM, et al. (2011) Distinct Patterns of IFITM-Mediated Restriction of Filoviruses, SARS Coronavirus, and Influenza A Virus. PLoS Pathog 7(1): e1001258. doi:10.1371/journal.ppat.1001258
Editor: Ralph S. Baric, University of North Carolina at Chapel Hill, United States of America
Received: April 27, 2010; Accepted: December 14, 2010; Published: January 6, 2011
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Funding: This work was supported by the New England Regional Center for Excellence/Biodefense and Emerging Infectious Disease (U54 AI057159), by the Burroughs Welcome Fund, and by Southeast Regional Center of Excellence for Emerging Infections and Biodefense (U54 AI057157). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, the US Department of Defense, the US Department of the Army or the institutions and companies affiliated with the authors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: I-Chueh_Huang@hms.harvard.edu (I-CH); farzan@hms.harvard.edu (MF)
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[Source: PLoS Pathogens, full text: <cite cite="http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001258?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+plospathogens%2FNewArticles+%28Ambra+-+Pathogens+New+Articles%29">PLoS Pathogens: Distinct Patterns of IFITM-Mediated Restriction of Filoviruses, SARS Coronavirus, and Influenza A Virus</cite>. Abstract, edited.]
Distinct Patterns of IFITM-Mediated Restriction of Filoviruses, SARS Coronavirus, and Influenza A Virus
l-Chueh Huang 1*, Charles C. Bailey 1, Jessica L. Weyer 1, Sheli R. Radoshitzky 2, Michelle M. Becker 3, Jessica J. Chiang 1, Abraham L. Brass 4, Asim A. Ahmed 5, Xiaoli Chi 2, Lian Dong 2, Lindsay E. Longobardi 2, Dutch Boltz 2, Jens H. Kuhn 6,7, Stephen J. Elledge 8, Sina Bavari 2, Mark R. Denison 3, Hyeryun Choe 5, Michael Farzan 1*
1 Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America,
2 US Army Medical Research Institute of Infectious Disease, National Interagency Biodefense Campus, Frederick, Maryland, United States of America,
3 Departments of Pediatrics and Microbiology and Immunology and Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America,
4 Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard Medical School, Charlestown, Massachusetts, United States of America,
5 Department of Pediatrics, Harvard Medical School, Children's Hospital, Boston, Massachusetts, United States of America,
6 Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Interagency Biodefense Campus, Frederick, Maryland, United States of America,
7 Tunnell Consulting Inc., King of Prussia, Pennsylvania, United States of America,
8 Department of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America
Abstract
Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM1, 2, and 3) are recently identified viral restriction factors that inhibit infection mediated by the influenza A virus (IAV) hemagglutinin (HA) protein. Here we show that IFITM proteins restricted infection mediated by the entry glycoproteins (GP1,2) of Marburg and Ebola filoviruses (MARV, EBOV). Consistent with these observations, interferon-β specifically restricted filovirus and IAV entry processes. IFITM proteins also inhibited replication of infectious MARV and EBOV. We observed distinct patterns of IFITM-mediated restriction: compared with IAV, the entry processes of MARV and EBOV were less restricted by IFITM3, but more restricted by IFITM1. Moreover, murine Ifitm5 and 6 did not restrict IAV, but efficiently inhibited filovirus entry. We further demonstrate that replication of infectious SARS coronavirus (SARS-CoV) and entry mediated by the SARS-CoV spike (S) protein are restricted by IFITM proteins. The profile of IFITM-mediated restriction of SARS-CoV was more similar to that of filoviruses than to IAV. Trypsin treatment of receptor-associated SARS-CoV pseudovirions, which bypasses their dependence on lysosomal cathepsin L, also bypassed IFITM- mediated restriction. However, IFITM proteins did not reduce cellular cathepsin activity or limit access of virions to acidic intracellular compartments. Our data indicate that IFITM-mediated restriction is localized to a late stage in the endocytic pathway. They further show that IFITM proteins differentially restrict the entry of a broad range of enveloped viruses, and modulate cellular tropism independently of viral receptor expression.
Author Summary
Cells express restriction factors, proteins whose primary activity is to inhibit viral replication. We have recently described a family of restriction factors, interferon-inducible transmembrane (IFITM) proteins, that interfere with replication of influenza A virus. The IFITM proteins uniquely inhibit replication early in the viral life-cycle, before the virus can successfully enter the cell cytoplasm. Here we show that the entry processes of several highly pathogenic viruses ? Marburg virus, Ebola virus, and SARS coronavirus ? are similarly disrupted by IFITM proteins. We compared IFITM-mediated restriction of these viruses with influenza A virus, and discovered that individual IFITM proteins are specialized for restriction. For example, we describe two mouse IFITM proteins that efficiently restrict entry of Marburg and Ebola viruses, but which do not inhibit influenza A virus. We further show that we can circumvent IFITM-mediated restriction by inducing a virus to enter a cell at or near the plasma membrane. This observation indicates that restriction is not a global property of the cell, but rather is localized to late endosomal and lysosomal compartments, the usual entry sites of IFITM-restricted viruses. This study therefore enhances our understanding of how the innate immune system controls influenza A virus and other pathogenic viruses.
Citation: Huang I-C, Bailey CC, Weyer JL, Radoshitzky SR, Becker MM, et al. (2011) Distinct Patterns of IFITM-Mediated Restriction of Filoviruses, SARS Coronavirus, and Influenza A Virus. PLoS Pathog 7(1): e1001258. doi:10.1371/journal.ppat.1001258
Editor: Ralph S. Baric, University of North Carolina at Chapel Hill, United States of America
Received: April 27, 2010; Accepted: December 14, 2010; Published: January 6, 2011
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Funding: This work was supported by the New England Regional Center for Excellence/Biodefense and Emerging Infectious Disease (U54 AI057159), by the Burroughs Welcome Fund, and by Southeast Regional Center of Excellence for Emerging Infections and Biodefense (U54 AI057157). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, the US Department of Defense, the US Department of the Army or the institutions and companies affiliated with the authors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: I-Chueh_Huang@hms.harvard.edu (I-CH); farzan@hms.harvard.edu (MF)
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