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-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 (A549) mainly through a RIG-I-dependent pathway, but IFN-λ-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-λ during influenza virus infection. Furthermore, we revealed that disruption of IFN-λ signaling pathway by increased SOCS-1 protein resulted in the activation of NF-κB and thereby enhanced the IFN-λ expression. Together, these data imply that suppression of IFN-λ signaling by virus-induced SOCS-1 causes an adaptive increase in IFN-λ expression by host to protect cells against the viral infection, as a consequence, leading to excessive production of IFN-λ with impaired antiviral response.

Induction of interferon lambda in influenza a virus infected cells treated with shRNAs against M1 transcript

“…However, in our case the immune stimulation by shM did not result in inhibition of IAV replication. Our results confirmed that IFN-λ could play a critical role in the pathogenesis of IAV and IFN-λ was induced through a RIG-1 -dependent pathway (Svetlikova et al, 2010;Okamoto et al, 2014;Wei et al, 2014). We conclude that shRNAs inhibited influenza virus infection in a gene-specific manner in cooperation with IFN-λ.…”

IFN-λ: A New Inducer of Local Immunity against Cancer and Infections

“…In comparison with IFN-α, IFN-λ is predominantly induced by respiratory viruses (28–31). Currently, IFN-λ is designated as a therapeutic candidate against the influenza A virus (IAV) infection (32, 33).…”

“…NS1 and NS2 proteins of the human RSV also inhibit IFN-λ production, occurring via IFN regulatory factor (IRF)-3, NF-κB, and proinflammatory cytokines suppression (36, 37). More recently, it has been reported that excessive expression of IFN-λ in the lung during IAV infection is associated with a suppression of IFN-λ signaling by SOCS-1 (31). The authors suggested that the suppression of cytokine signaling by virus-induced SOCS-1 leads to an adaptive increase in IFN-λ production by the host to protect cells against viral infection.…”

Robust Lys63-Linked Ubiquitination of RIG-I Promotes Cytokine Eruption in Early Influenza B Virus Infection

“…The interplay between influenza A virus and host innate immune signaling pathways has clearly been revealed to a great extent (16)(17)(18), but the regulatory mechanism of influenza B virus infection awaits further investigation. Currently, fundamental research has elucidated the interrelationship between influenza B virus and the host innate immune system.…”