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Nat Microbiol. 2016 Dec 5;2:16250. doi: 10.1038/nmicrobiol.2016.250.

Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells.

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Department of Plant Pathology &Microbiology, and Institute for Integrative Genome Biology, University of California, Riverside, California 92521, USA.
State Key Laboratory of Genetic Engineering, Collaborative Innovation Centre of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, China.
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Graduate Program in Genetics, Genomics, and Bioinformatics, University of California, Riverside, California 92521, USA.
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
Massachusetts General Hospital, Cancer Center and Center for Regenerative Medicine and Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521, USA.


Influenza A virus (IAV) causes annual epidemics and occasional pandemics, and is one of the best-characterized human RNA viral pathogens1. However, a physiologically relevant role for the RNA interference (RNAi) suppressor activity of the IAV non-structural protein 1 (NS1), reported over a decade ago2, remains unknown3. Plant and insect viruses have evolved diverse virulence proteins to suppress RNAi as their hosts produce virus-derived small interfering RNAs (siRNAs) that direct specific antiviral defence4-7 by an RNAi mechanism dependent on the slicing activity of Argonaute proteins (AGOs)8,9. Recent studies have documented induction and suppression of antiviral RNAi in mouse embryonic stem cells and suckling mice10,11. However, it is still under debate whether infection by IAV or any other RNA virus that infects humans induces and/or suppresses antiviral RNAi in mature mammalian somatic cells12-21. Here, we demonstrate that mature human somatic cells produce abundant virus-derived siRNAs co-immunoprecipitated with AGOs in response to IAV infection. We show that the biogenesis of viral siRNAs from IAV double-stranded RNA (dsRNA) precursors in infected cells is mediated by wild-type human Dicer and potently suppressed by both NS1 of IAV as well as virion protein 35 (VP35) of Ebola and Marburg filoviruses. We further demonstrate that the slicing catalytic activity of AGO2 inhibits IAV and other RNA viruses in mature mammalian cells, in an interferon-independent fashion. Altogether, our work shows that IAV infection induces and suppresses antiviral RNAi in differentiated mammalian somatic cells.

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