The Mammalian Response to Virus Infection Is Independent of Small RNA Silencing

• Direct comparison of mammalian IFN and small RNA responses to viral infection
• Engineering of a VP55-expressing virus to selectively degrade RISC-bound small RNAs
• Comprehensive analysis of virally induced RISC targets
• Characterization of the antiviral response in the absence of IFN and/or RISC function

SummaryA successful cellular response to virus infection is essential for evolutionary survival. In plants, arthropods, and nematodes, cellular antiviral defenses rely on RNAi. Interestingly, the mammalian response to virus is predominantly orchestrated through interferon (IFN)-mediated induction of antiviral proteins. Despite the potency of the IFN system, it remains unclear whether mammals also have the capacity to employ antiviral RNAi. Here, we investigated this by disabling IFN function, small RNA function, or both activities in the context of virus infection. We find that loss of small RNAs in the context of an in vivo RNA virus infection lowers titers due to reduced transcriptional repression of the host antiviral response. In contrast, enabling a virus with the capacity to inhibit the IFN system results in increased titers. Taken together, these results indicate that small RNA silencing is not a physiological contributor to the IFN-mediated cellular response to virus infection.

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