IFITM3 Inhibits Influenza A Virus Infection by Preventing Cytosolic Entry

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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. Influenza epidemics exact a great toll on world health. Thus research to identify new anti-influenza virus strategies would be useful. Each of our cells contains antiviral factors that work to inhibit infection. A large component of this antiviral program is regulated by the interferon family of signaling molecules. Here, we seek to better understand how one of these antiviral factors, IFITM3, contributes to both baseline, as well as interferon-induced, antagonism of influenza A viral infection. We found that interferon prevents influenza A virus from entering our cells by blocking the virus' fusion with the cellular membrane. Furthermore, we learned that IFITM3 is required for this antiviral action of interferon, and that high levels of IFITM3 alone can produce a similar viral inhibition. Together, these results improve our understanding of how IFITM3 serves to defend us against viral invasion at a very early stage of infection.