title: IFITM3 inhibits influenza A virus infection by preventing cytosolic entry.
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.
authors: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Charlestown, Massachusetts, United States of America.
authors: Eric M
authors: EM
authors: Feeley
authors: Jennifer S
authors: JS
authors: Sims
authors: Sinu P
authors: SP
authors: John
authors: Christopher R
authors: CR
authors: Chin
authors: Thomas
authors: T
authors: Pertel
authors: Li-Mei
authors: LM
authors: Chen
authors: Gaurav D
authors: GD
authors: Gaiha
authors: Bethany J
authors: BJ
authors: Ryan
authors: Ruben O
authors: RO
authors: Donis
authors: Stephen J
authors: SJ
authors: Elledge
authors: Abraham L
authors: AL
authors: Brass
mesh_terms: D000818:Animals; D002645:Chickens; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication
chemical_list: C080082:IFITM3 protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D007371:Interferon-gamma