Journal
CELL RESEARCH
Volume 23, Issue 5, Pages 673-690Publisher
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2013.47
Keywords
antiviral; cell signaling; innate immunity; inflammation; NADPH oxidase; interferon
Categories
Funding
- Canadian Institutes of Health Research (CIHR, Canada) [MOP89807]
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Fonds de la Recherche en Sante du Quebec (FRSQ, Canada)
- FRSQ
- CIHR
- Tier II Canada Research Chairs
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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 IFN beta 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 IFN beta and TNF alpha, 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.
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