Suppression of Interferon Lambda Signaling by SOCS-1 Results in Their Excessive Production during Influenza Virus Infection

Haitao Wei1, Song Wang, Qinghuang Chen, Yuhai Chen, Xiaojuan Chi Lianfeng Zhang, Shile Huang, George F. Gao, Ji-Long Chen

PLoS Pathog 10(1): e1003845

Speaker: Yi-Sheng Kao (高宜聲)                                      Time: 14:00~15:00, Mar.25, 2015

Commentator: Dr. Chia-Yi Yu (余佳益 老師)        Place: Room 601

Abstract:

   The clearance of virus during the infection depends on the activation of effective innate and adaptive immune responses, such as interferons (IFN) response. Unfortunately, virus is able to develop some strategies to disrupt the host immune system. For instance, during Influenza A virus (IAV) infection, virus induce excessive cytokine production (cytokine storm) in order to dysregulate immune response on behalf to progress its pathogenesis. In the earlier, authors using the cDNA microarray has shown a substantial increase in type III IFNs (IFN-λ) during the progression of IAV infection. IFN-λ, like type I IFN, is renowned to activate the JAK-STAT signal pathway to achieve its antiviral function.(1) However, the mechanisms underlying the overproduction of IFN-λ during IAV infection are still unclear. Initially, they have found that silencing of RIG-I in A549 cells has showed decrease in the production of IFN-λ induced by IAV infection. This data has suggested that virus is able to induce excessive production of IFN-λ via RIG-I mediated pathway. Nevertheless, IFN-λ induced phosphorylation of the STAT1 was dramatically inhibited in the infected cells. Therefore, authors have speculated that suppressor of cytokine signalling 1 (SOCS-1), a negative regulator of JAK-STAT could be possibly involved in the suppression of STAT1 activation during the persistence of infection. Interestingly, as expected, IAV infection is able to show an immense up-regulation of SOCS-1 production which is cytokine-independent during its early stage of infection. Moreover, either disruption of the SOCS-1 expression or forced activation of STAT1 can significantly reduce the production of IFN-λ in vitro and in vivo. Furthermore, they also revealed that increased expression of SOCS-1 resulted in the activation NF-κB to enhance the IFN-λ expression. In conclusion, IAV induce hypercytokinemia is due to production of immoderate SOCS-1 contributing to the inhibition of IFN-λ signaling pathway, which as a consequence, leading the host to excessive production of IFN- λ with impaired antiviral response.

Reference:

1.   Jewell NA, et al. (2010) Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo. J Virol 84: 11515–11522.