Abstract
The type I interferon (IFN) system is a first line of defense against viral infections. Viruses have developed various mechanisms to counteract this response. So far, the interferon antagonistic activity of influenza A viruses was mainly observed on the level of IFNβ gene induction via action of the viral non-structural protein 1 (NS1). Here we present data indicating that influenza A viruses not only suppress IFNβ gene induction but also inhibit type I IFN signaling through a mechanism involving induction of the suppressor of cytokine signaling-3 (SOCS-3) protein. Our study was based on the observation that in cells that were infected with influenza A virus and subsequently stimulated with IFNα/β, phosphorylation of the signal transducer and activator of transcription protein 1 (STAT1) was strongly reduced. This impaired STAT1 activation was not due to the action of viral proteins but rather appeared to be induced by accumulation of viral 5′ triphosphate RNA in the cell. SOCS proteins are potent endogenous inhibitors of Janus kinase (JAK)/STAT signaling. Closer examination revealed that SOCS-3 but not SOCS-1 mRNA levels increase in an RNA- and nuclear factor kappa B (NF-κB)-dependent but type I IFN-independent manner early in the viral replication cycle. This direct viral induction of SOCS-3 mRNA and protein expression appears to be relevant for suppression of the antiviral response since in SOCS-3 deficient cells a sustained phosphorylation of STAT1 correlated with elevated expression of type I IFN-dependent genes. As a consequence, progeny virus titers were reduced in SOCS-3 deficient cells or in cells were SOCS-3 expression was knocked-down by siRNA. These data provide the first evidence that influenza A viruses suppress type I IFN signaling on the level of JAK/STAT activation. The inhibitory effect is at least in part due to the induction of SOCS-3 gene expression, which results in an impaired antiviral response.
Highlights
Influenza A viruses are negative-stranded RNA viruses that belong to the family of orthomyxoviruses
This is a novel mechanism by which influenza viruses inhibit the antiviral response of the host and paves the path to efficient virus replication
Phosphorylation of STAT1 and STAT2 by members of the Janus kinase (JAK) tyrosine kinase family is a prerequisite for activation of these transcription factors to drive type I IFN-induced gene expression
Summary
Influenza A viruses are negative-stranded RNA viruses that belong to the family of orthomyxoviruses. Among the influenza viral proteins, the NS1 has been identified as the main type I IFN antagonistic factor. Two major mechanisms have been described by which NS1 suppresses the initial expression of IFNb. On the one hand NS1 inhibits vRNAmediated induction of the transcription factors interferon regulatory factor-3 (IRF-3), activating protein–1 (AP-1) and NFkB that target the IFNb promoter. On the one hand NS1 inhibits vRNAmediated induction of the transcription factors interferon regulatory factor-3 (IRF-3), activating protein–1 (AP-1) and NFkB that target the IFNb promoter This most likely occurs via binding to the RNA-sensor retinoic acid inducible gene (RIG-I) and inhibition of RIG-I-mediated signaling in response to viral RNA [1,2]. Other functions of the multifunctional protein include block of activation of the dsRNAactivated protein kinase PKR by direct interaction [6] or activation of the phosphatidylinositol-3 kinase PI3K/Akt pathway to prevent premature apoptosis induction [7,8]
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