Publication Date:
2013-11-29
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077721/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077721/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schoggins, John W -- MacDuff, Donna A -- Imanaka, Naoko -- Gainey, Maria D -- Shrestha, Bimmi -- Eitson, Jennifer L -- Mar, Katrina B -- Richardson, R Blake -- Ratushny, Alexander V -- Litvak, Vladimir -- Dabelic, Rea -- Manicassamy, Balaji -- Aitchison, John D -- Aderem, Alan -- Elliott, Richard M -- Garcia-Sastre, Adolfo -- Racaniello, Vincent -- Snijder, Eric J -- Yokoyama, Wayne M -- Diamond, Michael S -- Virgin, Herbert W -- Rice, Charles M -- 099220/Wellcome Trust/United Kingdom -- AI057158/AI/NIAID NIH HHS/ -- AI057160/AI/NIAID NIH HHS/ -- AI083025/AI/NIAID NIH HHS/ -- AI091707/AI/NIAID NIH HHS/ -- AI095611/AI/NIAID NIH HHS/ -- AI104972/AI/NIAID NIH HHS/ -- DK095031/DK/NIDDK NIH HHS/ -- G0801822/Medical Research Council/United Kingdom -- GM076547/GM/NIGMS NIH HHS/ -- GM103511/GM/NIGMS NIH HHS/ -- HHSN266200700010C/PHS HHS/ -- HHSN272200900041CU19/CU/CSP VA/ -- K01 DK095031/DK/NIDDK NIH HHS/ -- R00 AI095320/AI/NIAID NIH HHS/ -- R01 AI032972/AI/NIAID NIH HHS/ -- R01 AI091707/AI/NIAID NIH HHS/ -- R01 AI102597/AI/NIAID NIH HHS/ -- R01 AI104972/AI/NIAID NIH HHS/ -- T32 AI005284/AI/NIAID NIH HHS/ -- T32 AR007279/AR/NIAMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jan 30;505(7485):691-5. doi: 10.1038/nature12862. Epub 2013 Nov 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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.). ; Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065, USA. ; Rheumatology Division, Department of Medicine, and Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Infectious Diseases Division, Department of Medicine and Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Seattle Biomedical Research Institute, Seattle, Washington 98109, USA [2] Institute for Systems Biology, Seattle, Washington 98109, USA. ; Seattle Biomedical Research Institute, Seattle, Washington 98109, USA. ; Department of Microbiology and Immunology, Columbia University, New York, New York 10032, USA. ; Department of Microbiology, University of Chicago, Chicago, Illinois 60637, USA. ; 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.). ; 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. ; Department of Medical Microbiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24284630" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cluster Analysis
;
DNA Viruses/immunology/pathogenicity
;
Flow Cytometry
;
Gene Library
;
Immunity, Innate/*genetics/*immunology
;
Interferon Regulatory Factor-3/immunology/metabolism
;
Interferons/*immunology/metabolism
;
Membrane Proteins/metabolism
;
Mice
;
Mice, Knockout
;
Nucleotidyltransferases/deficiency/genetics/*immunology/*metabolism
;
RNA Viruses/immunology/pathogenicity
;
STAT1 Transcription Factor/metabolism
;
Substrate Specificity
;
Viruses/classification/*immunology/pathogenicity
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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