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Suppression of interferon lambda signaling by SOCS-1 results in their excessive production during influenza virus infection.

ABSTRACT: Innate cytokine response provides the first line of defense against influenza virus infection. However, excessive production of cytokines appears to be critical in the pathogenesis of influenza virus. Interferon lambdas (IFN-?) have been shown to be overproduced during influenza virus infection, but the precise pathogenic processes of IFN-? production have yet to be characterized. In this report, we observed that influenza virus induced robust expression of IFN-? in alveolar epithelial cells (A549) mainly through a RIG-I-dependent pathway, but IFN-?-induced phosphorylation of the signal transducer and activator of transcription protein 1 (STAT1) was dramatically inhibited in the infected cells. Remarkably, influenza virus infection induced robust expression of suppressor of cytokine signaling-1 (SOCS-1), leading to inhibition of STAT1 activation. Interestingly, the virus-induced SOCS-1 expression was cytokine-independent at early stage of infection both in vitro and in vivo. Using transgenic mouse model and distinct approaches altering the expression of SOCS-1 or activation of STAT signaling, we demonstrated that disruption of the SOCS-1 expression or expression of constitutively active STAT1 significantly reduced the production of IFN-? during influenza virus infection. Furthermore, we revealed that disruption of IFN-? signaling pathway by increased SOCS-1 protein resulted in the activation of NF-?B and thereby enhanced the IFN-? expression. Together, these data imply that suppression of IFN-? signaling by virus-induced SOCS-1 causes an adaptive increase in IFN-? expression by host to protect cells against the viral infection, as a consequence, leading to excessive production of IFN-? with impaired antiviral response.

SUBMITTER: Wei H

PROVIDER: S-EPMC3879354 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Suppression of interferon lambda signaling by SOCS-1 results in their excessive production during influenza virus infection.

Wei Haitao H Wang Song S Chen Qinghuang Q Chen Yuhai Y Chi Xiaojuan X Zhang Lianfeng L Huang Shile S Gao George F GF Chen Ji-Long JL

PLoS pathogens 20140102 1

Innate cytokine response provides the first line of defense against influenza virus infection. However, excessive production of cytokines appears to be critical in the pathogenesis of influenza virus. Interferon lambdas (IFN-λ) have been shown to be overproduced during influenza virus infection, but the precise pathogenic processes of IFN-λ production have yet to be characterized. In this report, we observed that influenza virus induced robust expression of IFN-λ in alveolar epithelial cells (A5 ...[more]

PMID: 24391501

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Project description:We have shown that membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1), a scaffold protein with six PSD95/DiscLarge/ZO-1 (PDZ) domains, is involved in the regulation of endothelial cell (EC) activation and atherogenesis in mice. In addition to causing acute respiratory disease, influenza A virus (IAV) infection plays an important role in atherogenesis and triggers acute coronary syndromes and fatal myocardial infarction. Therefore, the aim of this study is to investigate the function and regulation of MAGI1 in IAV-induced EC activation. Whereas, EC infection by IAV increases MAGI1 expression, MAGI1 depletion suppresses IAV infection, suggesting that the induction of MAGI1 may promote IAV infection. Treatment of ECs with oxidized low-density lipoprotein (OxLDL) increases MAGI1 expression and IAV infection, suggesting that MAGI1 is part of the mechanistic link between serum lipid levels and patient prognosis following IAV infection. Our microarray studies suggest that MAGI1-depleted ECs increase protein expression and signaling networks involve in interferon (IFN) production. Specifically, infection of MAGI1-null ECs with IAV upregulates expression of signal transducer and activator of transcription 1 (STAT1), interferon b1 (IFNb1), myxovirus resistance protein 1 (MX1) and 2'-5'-oligoadenylate synthetase 2 (OAS2), and activate STAT5. By contrast, MAGI1 overexpression inhibits Ifnb1 mRNA and MX1 expression, again supporting the pro-viral response mediated by MAGI1. MAGI1 depletion induces the expression of MX1 and virus suppression. The data suggests that IAV suppression by MAGI1 depletion may, in part, be due to MX1 induction. Lastly, interferon regulatory factor 3 (IRF3) translocates to the nucleus in the absence of IRF3 phosphorylation, and IRF3 SUMOylation is abolished in MAGI1-depleted ECs. The data suggests that MAGI1 inhibits IRF3 activation by maintaining IRF3 SUMOylation. In summary, IAV infection occurs in ECs in a MAGI1 expression-dependent manner by inhibiting anti-viral responses including STATs and IRF3 activation and subsequent MX1 induction, and MAGI1 plays a role in EC activation, and in upregulating a pro-viral response. Therefore, the inhibition of MAGI1 is a potential therapeutic target for IAV-induced cardiovascular disease.

Dataset Information

Suppression of interferon lambda signaling by SOCS-1 results in their excessive production during influenza virus infection.

Publications

Suppression of interferon lambda signaling by SOCS-1 results in their excessive production during influenza virus infection.

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