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 H 2 O 2 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.

Expression regulation of zebrafish interferon regulatory factor 9 by promoter analysis

“…However, there is still an overlapping set of genes induced by both types of IFNs (Sanda et al, 2006), reflecting the complexity of regulatory sequences of ISGs. Consistently, some ISGs can be induced by non-canonic JAK-STAT signaling pathway under IFN treatments (Fink et al, 2013;Lou et al, 2009;Rani et al, 2010).…”

Noncanonical Effects of IRF9 in Intestinal Inflammation: More than Type I and Type III Interferons

“…Noncanonical assemblies of Stats and their associates have been described in other situations as well. For example, Stat2-IRF9 complexes exert transcriptional activity independently of Stat1 in the antiviral response (7,9,11). In addition, unphosphorylated Stat complexes were described (U-STATs) (51), and the ISGF3 II complex containing phosphorylated Stat1 in association with unphosphorylated Stat2 and IRF9 subunits was described as a mediator of delayed gene induction by IFN-␥ (10).…”

Different STAT Transcription Complexes Drive Early and Delayed Responses to Type I IFNs

“…Unexpectedly, IFN-Is lost their ability to suppress L. pneumophila growth in these macrophages, suggesting that Stat1 and Stat2 function redundantly in their ability to mediate this response. Although the mechanism by which Stat1 independently signals is well understood (i.e., Stat1 homodimers; (5)), the mechanism by which Stat2 signals independently of Stat1 has not been fully characterized (19-25). The current study exploits primary Stat1[−/−] macrophages to explore this “Stat2-only” pathway.…”