title: Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity.
abstract: The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.
authors.affiliation: 1] Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065, USA [2] Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA (J.W.S.); MRC-University of Glasgow Centre for Virus Research, Glasgow, Scotland G61 1QH, UK (R.M.E.).
authors.forename: John W
authors.initials: JW
authors.lastname: Schoggins
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Donna A
authors.initials: DA
authors.lastname: MacDuff
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Imanaka
authors.affiliation: Rheumatology Division, Department of Medicine, and Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Gainey
authors.affiliation: Infectious Diseases Division, Department of Medicine and Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Bimmi
authors.initials: B
authors.lastname: Shrestha
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Eitson
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Katrina B
authors.initials: KB
authors.lastname: Mar
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: R Blake
authors.initials: RB
authors.lastname: Richardson
authors.affiliation: 1] Seattle Biomedical Research Institute, Seattle, Washington 98109, USA [2] Institute for Systems Biology, Seattle, Washington 98109, USA.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ratushny
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington 98109, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Litvak
authors.affiliation: Department of Microbiology and Immunology, Columbia University, New York, New York 10032, USA.
authors.forename: Rea
authors.initials: R
authors.lastname: Dabelic
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Balaji
authors.initials: B
authors.lastname: Manicassamy
authors.affiliation: 1] Seattle Biomedical Research Institute, Seattle, Washington 98109, USA [2] Institute for Systems Biology, Seattle, Washington 98109, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Aitchison
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington 98109, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
authors.affiliation: 1] School of Biology, University of St Andrews, St Andrews, Scotland KY16 9ST, UK [2] Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA (J.W.S.); MRC-University of Glasgow Centre for Virus Research, Glasgow, Scotland G61 1QH, UK (R.M.E.).
authors.forename: Richard M
authors.initials: RM
authors.lastname: Elliott
authors.affiliation: 1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Department of Microbiology and Immunology, Columbia University, New York, New York 10032, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Racaniello
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Snijder
authors.affiliation: Rheumatology Division, Department of Medicine, and Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
authors.affiliation: 1] Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA [2] Infectious Diseases Division, Department of Medicine and Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D004267:DNA Viruses / Q000276:immunology / Q000472:pathogenicity; D005434:Flow Cytometry; D015723:Gene Library; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism; D007372:Interferons / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009713:Nucleotidyltransferases / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D012328:RNA Viruses / Q000276:immunology / Q000472:pathogenicity; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013379:Substrate Specificity; D014780:Viruses / Q000145:classification / Q000276:immunology* / Q000472:pathogenicity; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D050838:Interferon Regulatory Factor-3; D007372:Interferons; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D050794:STAT1 Transcription Factor; C494233:Irf3 protein, mouse; C494080:Stat1 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase