IFITM3 Inhibits Influenza A Virus Infection by Preventing Cytosolic Entry
Eric M. Feeley,Jennifer S. Sims,Sinu P. John,Christopher R. Chin,Thomas Pertel,Li-Mei Chen,Gaurav D. Gaiha,Bethany J. Ryan,Ruben O. Donis,Stephen J. Elledge,Stephen J. Elledge,Abraham L. Brass,Abraham L. Brass +12 more
TLDR
It is reported that IFN prevents emergence of viral genomes from the endosomal pathway, and that IFITM3 is both necessary and sufficient for this function.Abstract:
To replicate, viruses must gain access to the host cell's resources. Interferon (IFN) regulates the actions of a large complement of interferon effector genes (IEGs) that prevent viral replication. The interferon inducible transmembrane protein family members, IFITM1, 2 and 3, are IEGs required for inhibition of influenza A virus, dengue virus, and West Nile virus replication in vitro. Here we report that IFN prevents emergence of viral genomes from the endosomal pathway, and that IFITM3 is both necessary and sufficient for this function. Notably, viral pseudoparticles were inhibited from transferring their contents into the host cell cytosol by IFN, and IFITM3 was required and sufficient for this action. We further demonstrate that IFN expands Rab7 and LAMP1-containing structures, and that IFITM3 overexpression is sufficient for this phenotype. Moreover, IFITM3 partially resides in late endosomal and lysosomal structures, placing it in the path of invading viruses. Collectively our data are consistent with the prediction that viruses that fuse in the late endosomes or lysosomes are vulnerable to IFITM3's actions, while viruses that enter at the cell surface or in the early endosomes may avoid inhibition. Multiple viruses enter host cells through the late endocytic pathway, and many of these invaders are attenuated by IFN. Therefore these findings are likely to have significance for the intrinsic immune system's neutralization of a diverse array of threats.read more
Citations
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Journal ArticleDOI
Interferon-Stimulated Genes: A Complex Web of Host Defenses
TL;DR: This review begins by introducing interferon (IFN) and the JAK-STAT signaling pathway to highlight features that impact ISG production and describes ways in which ISGs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the Jak-STAT pathway.
Journal ArticleDOI
IFITM3 restricts the morbidity and mortality associated with influenza
Aaron R. Everitt,Simon Clare,Thomas Pertel,Sinu P. John,Rachael S. Wash,Sarah E. Smith,Christopher R. Chin,Eric M. Feeley,Jennifer S. Sims,David J. Adams,Helen M. Wise,Leanne Kane,David Goulding,Paul Digard,Verneri Anttila,J Kenneth Baillie,Timothy S. Walsh,David A. Hume,Aarno Palotie,Yali Xue,Vincenza Colonna,Vincenza Colonna,Chris Tyler-Smith,Jake Dunning,Stephen B. Gordon,Rosalind L. Smyth,Peter J. M. Openshaw,Gordon Dougan,Abraham L. Brass,Abraham L. Brass,Paul Kellam,Paul Kellam +31 more
TL;DR: Data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.
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The broad-spectrum antiviral functions of IFIT and IFITM proteins
TL;DR: This Review focuses on recent advances in identifying the unique mechanisms of action of IFIT and IFITM proteins, which explain their broad-spectrum activity against the replication, spread and pathogenesis of a range of human viruses.
Journal ArticleDOI
Intrinsic antiviral immunity
Nan Yan,Zhijian J. Chen +1 more
TL;DR: This review focuses on recent advances in understanding of the roles of intrinsic antiviral factors that restrict infection by human immunodeficiency virus and influenza virus.
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Interferon-inducible effector mechanisms in cell-autonomous immunity.
TL;DR: Recent genomic and subgenomic analyses have begun to assign functional properties to novel IFN-inducible effector proteins that restrict bacteria, protozoa and viruses in different subcellular compartments and at different stages of the pathogen life cycle.
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The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus
Abraham L. Brass,Abraham L. Brass,Abraham L. Brass,I-Chueh Huang,Yair Benita,Sinu P. John,Manoj N. Krishnan,Eric M. Feeley,Bethany J. Ryan,Jessica L. Weyer,Louise van der Weyden,Erol Fikrig,David J. Adams,Ramnik J. Xavier,Michael Farzan,Stephen J. Elledge +15 more
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