IFITM3 Inhibits Influenza A Virus Infection by Preventing Cytosolic Entry

PLoS Pathogens

Stephen J. Elledge¹  Abraham L. Brass²  Li-Mei Chen³  Ruben O. Donis³  Eric M. Feeley⁴  Jennifer S. Sims⁴  Sinu P. John⁴  Bethany J. Ryan⁴  Thomas Pertel⁴  Gaurav D. Gaiha⁴  Christopher R. Chin⁴ 

[1] Department of Genetics, Harvard Medical School, Department of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, United States of America;Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America;Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America;Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Charlestown, Massachusetts, United States of America

关键词: Influenza A virus;    Cell staining;    Cell fusion;    Lysosomes;    Dengue virus;    Influenza;    Viral replication;    Interferons;   

DOI  :  10.1371/journal.ppat.1002337

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY