title: IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH oxidase-mediated airway antiviral response.
abstract: Airway epithelial cells are key initial innate immune responders in the fight against respiratory viruses, primarily via the secretion of antiviral and proinflammatory cytokines that act in an autocrine/paracrine fashion to trigger the establishment of an antiviral state. It is currently thought that the early antiviral state in airway epithelial cells primarily relies on IFNβ secretion and the subsequent activation of the interferon-stimulated gene factor 3 (ISGF3) transcription factor complex, composed of STAT1, STAT2 and IRF9, which regulates the expression of a panoply of interferon-stimulated genes encoding proteins with antiviral activities. However, the specific pathways engaged by the synergistic action of different cytokines during viral infections, and the resulting physiological outcomes are still ill-defined. Here, we unveil a novel delayed antiviral response in the airways, which is initiated by the synergistic autocrine/paracrine action of IFNβ and TNFα, and signals through a non-canonical STAT2- and IRF9-dependent, but STAT1-independent cascade. This pathway ultimately leads to the late induction of the DUOX2 NADPH oxidase expression. Importantly, our study uncovers that the development of the antiviral state relies on DUOX2-dependent H2O2 production. Key antiviral pathways are often targeted by evasion strategies evolved by various pathogenic viruses. In this regard, the importance of the novel DUOX2-dependent antiviral pathway is further underlined by the observation that the human respiratory syncytial virus is able to subvert DUOX2 induction.
authors.affiliation: Centre de Recherche du CHUM (CRCHUM), Montréal, Québec, Canada.
authors.forename: Karin
authors.initials: K
authors.lastname: Fink
authors.forename: Lydie
authors.initials: L
authors.lastname: Martin
authors.forename: Esperance
authors.initials: E
authors.lastname: Mukawera
authors.forename: Stéfany
authors.initials: S
authors.lastname: Chartier
authors.forename: Xavier
authors.initials: X
authors.lastname: De Deken
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Brochiero
authors.forename: Françoise
authors.initials: F
authors.lastname: Miot
authors.forename: Nathalie
authors.initials: N
authors.lastname: Grandvaux
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects; D002460:Cell Line; D004357:Drug Synergism; D000074623:Dual Oxidases; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D020733:RNA, Small Cytoplasmic / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D012136:Respiratory Syncytial Viruses / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D029082:Sendai virus / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; C507964:IFNAR1 protein, human; C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D012333:RNA, Messenger; D020733:RNA, Small Cytoplasmic; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D006861:Hydrogen Peroxide; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human
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