Andrew Mehle, University of Wisconsin-Madison

Repurposing Canonical Antiviral Responses to Promote Viral Infection

Cells infected by influenza virus mount a large-scale antiviral response and most ultimately initiate cell death pathways in an attempt to suppress viral replication. During a CRISPR knockout screen designed to query post-entry steps during infection, we identified a large class of presumptive antiviral factors, including IFIT2, as important enhancers of influenza virus replication. IFIT2 is an interferon stimulated gene with well-established antiviral function for some viruses. Contrary to expectations, we show here that IFIT2 is instead repurposed by influenza virus to support viral replication. IFIT2 interacts with viral RNAs, the viral nucleoprotein, and translating ribosomes to enhance viral gene expression and replication. IFIT2 also stimulates virally-induced apoptosis. Cells lacking IFIT2 fail to undergo apoptosis and survive infection. Remarkably, genetic and chemical ablation of apoptosis further reduced viral yield. Our results suggest that influenza virus has evolved to exploit the antiviral and apoptotic cellular environment, redirecting these classically antiviral events into pro-viral effectors, a process we termed “going pro.” Moreover, it is highly unlikely that the re-purposing of antiviral genes is specific to influenza A virus, but rather is generalizable to additional viruses and other antiviral viral proteins defining a new interface between the virus and host.

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