title: Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses.
abstract: Stimulator of interferon genes (STING) is known be involved in control of DNA viruses but has an unexplored role in control of RNA viruses. During infection with DNA viruses STING is activated downstream of cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses, including influenza A virus (IAV). Further, IAV interacts with STING through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP antagonizes interferon production induced by membrane fusion or IAV but not by cGAMP or DNA. Similar to the enveloped RNA viruses, membrane fusion stimulates interferon production in a STING-dependent but cGAS-independent manner. Abolishment of this pathway led to reduced interferon production and impaired control of enveloped RNA viruses. Thus, enveloped RNA viruses stimulate a cGAS-independent STING pathway, which is targeted by IAV.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Holm
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Stine H
authors.initials: SH
authors.lastname: Rahbek
authors.affiliation: Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.|Department of Molecular Biology and Genetics, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Hans Henrik
authors.initials: HH
authors.lastname: Gad
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Rasmus O
authors.initials: RO
authors.lastname: Bak
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jakobsen
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts, Amherst, Massachusetts M01003, USA.
authors.forename: Zhaozaho
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Anne Louise
authors.initials: AL
authors.lastname: Hansen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Simon K
authors.initials: SK
authors.lastname: Jensen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Thomsen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Laustsen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Camilla G
authors.initials: CG
authors.lastname: Nielsen
authors.affiliation: Psychiatric Department, Aarhus University Hospital, Aarhus 8000, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Severinsen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Yingluo
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Dara L
authors.initials: DL
authors.lastname: Burdette
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Department of Medical Microbiology, University Medical Center, Utrecht 3508GA, The Netherlands.
authors.forename: Robert Jan
authors.initials: RJ
authors.lastname: Lebbink
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus 8000, Denmark.|Skauvaccines, Aarhus Nord 8200, Denmark.
authors.forename: Mogens
authors.initials: M
authors.lastname: Duch
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts, Amherst, Massachusetts M01003, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus 8000, Denmark.|Skauvaccines, Aarhus Nord 8200, Denmark.
authors.forename: Shervin
authors.initials: S
authors.lastname: Bahrami
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Jakob Giehm
authors.initials: JG
authors.lastname: Mikkelsen
authors.affiliation: Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.|Department of Molecular Biology and Genetics, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Rune
authors.initials: R
authors.lastname: Hartmann
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.|Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
mesh_terms: D000818:Animals; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000502:physiology*; D007251:Influenza, Human / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D012327:RNA Virus Infections / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D012328:RNA Viruses / Q000235:genetics / Q000502:physiology; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D007370:Interferon Type I; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C578391:cGAS protein, mouse