title: Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway.
abstract: Modified vaccinia virus Ankara (MVA) is an attenuated poxvirus that has been engineered as a vaccine against infectious agents and cancers. Our goal is to understand how MVA modulates innate immunity in dendritic cells (DCs), which can provide insights to vaccine design. In this study, using murine bone marrow-derived dendritic cells, we assessed type I interferon (IFN) gene induction and protein secretion in response to MVA infection. We report that MVA infection elicits the production of type I IFN in murine conventional dendritic cells (cDCs), but not in plasmacytoid dendritic cells (pDCs). Transcription factors IRF3 (IFN regulatory factor 3) and IRF7, and the positive feedback loop mediated by IFNAR1 (IFN alpha/beta receptor 1), are required for the induction. MVA induction of type I IFN is fully dependent on STING (stimulator of IFN genes) and the newly discovered cytosolic DNA sensor cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase). MVA infection of cDCs triggers phosphorylation of TBK1 (Tank-binding kinase 1) and IRF3, which is abolished in the absence of cGAS and STING. Furthermore, intravenous delivery of MVA induces type I IFN in wild-type mice, but not in mice lacking STING or IRF3. Treatment of cDCs with inhibitors of endosomal and lysosomal acidification or the lysosomal enzyme Cathepsin B attenuated MVA-induced type I IFN production, indicating that lysosomal enzymatic processing of virions is important for MVA sensing. Taken together, our results demonstrate a critical role of the cGAS/STING-mediated cytosolic DNA-sensing pathway for type I IFN induction in cDCs by MVA. We present evidence that vaccinia virulence factors E3 and N1 inhibit the activation of IRF3 and the induction of IFNB gene in MVA-infected cDCs.
authors.affiliation: Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America; Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Peihong
authors.initials: P
authors.lastname: Dai
authors.affiliation: Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America; Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Cao
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Francesca
authors.initials: F
authors.lastname: Avogadri
authors.affiliation: Institute for Virology, Düsseldorf University Hospital, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Lianpan
authors.initials: L
authors.lastname: Dai
authors.affiliation: Institute for Virology, Düsseldorf University Hospital, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Drexler
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
authors.affiliation: Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America; Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Stewart
authors.initials: S
authors.lastname: Shuman
authors.affiliation: Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America; Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Liang
authors.initials: L
authors.lastname: Deng
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D011992:Endosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate / Q000235:genetics; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008247:Lysosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009713:Nucleotidyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014615:Vaccinia / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D053633:Receptor, Interferon alpha-beta; D014764:Viral Proteins; D037521:Virulence Factors; C081374:E3L protein, Vaccinia virus; C508032:Ifnar1 protein, mouse; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C498588:Tbk1 protein, mouse; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
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