title: Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells.
abstract: 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 defence4-7by 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.
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Megha
authors.initials: M
authors.lastname: Basavappa
authors.affiliation: Department of Plant Pathology &Microbiology, and Institute for Integrative Genome Biology, University of California, Riverside, California 92521, USA.|Graduate Program in Genetics, Genomics, and Bioinformatics, University of California, Riverside, California 92521, USA.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Plant Pathology &Microbiology, and Institute for Integrative Genome Biology, University of California, Riverside, California 92521, USA.
authors.forename: Shuwei
authors.initials: S
authors.lastname: Dong
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: D Alexander
authors.initials: DA
authors.lastname: Cronkite
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Prior
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Reinecker
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Hertzog
authors.affiliation: Department of Plant Pathology &Microbiology, and Institute for Integrative Genome Biology, University of California, Riverside, California 92521, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Plant Pathology &Microbiology, and Institute for Integrative Genome Biology, University of California, Riverside, California 92521, USA.
authors.forename: Wan-Xiang
authors.initials: WX
authors.lastname: Li
authors.affiliation: Massachusetts General Hospital, Cancer Center and Center for Regenerative Medicine and Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
authors.forename: Sihem
authors.initials: S
authors.lastname: Cheloufi
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521, USA.
authors.forename: Fedor V
authors.initials: FV
authors.lastname: Karginov
authors.affiliation: Department of Plant Pathology &Microbiology, and Institute for Integrative Genome Biology, University of California, Riverside, California 92521, USA.|Graduate Program in Genetics, Genomics, and Bioinformatics, University of California, Riverside, California 92521, USA.
authors.forename: Shou-Wei
authors.initials: SW
authors.lastname: Ding
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Jeffrey
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D011485:Protein Binding; D034622:RNA Interference; D012367:RNA, Viral / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors
chemical_list: D060565:Argonaute Proteins; C085820:INS1 protein, influenza virus; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins