超级IL-6复合物形成机制及其在宿主抗病毒应答中的功能研究

病毒感染诱导白介素6(IL-6)及其可溶性受体(sIL-6R)上调表达。我们前期研究工作发现sIL-6R在流感病毒诱导的炎症应答中上调IL-6、IL-32表达，并形成正调控和负反馈抑制网络。同时，sIL-6R与IL-27/p28亚基形成复合物并在宿主抗病毒天然免疫中发挥重要作用。在病毒感染过程中IL-6、sIL-6R、p28、EBI3之间发生错综复杂的两两蛋白互作，形成一个多聚体超级白介素6复合物(sIL-6c)。我们的发现大大超出了以前对IL-6及其受体的认知。本课题将在前期工作基础上从多个角度研究sIL-6c形成的分子机制；然后从细胞水平和动物水平分别探究sIL-6c对DNA和RNA病毒复制的影响，在宿主抗病毒天然免疫反应中的作用；揭示sIL-6c在病毒感染过程对其它细胞因子表达的影响及其介导的炎症反应网络调控机制。该课题的顺利实施将为病毒感染性疾病的治疗提供新的思路和策略。

Viral infection can induce the expression of both interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R). The two modes of IL-6 activation are presented as either classical IL-6 activation via membrane-bound IL6R (classical IL-6 signaling) or sIL6R-mediated cell signaling (IL-6 trans-signaling). Our previous study indicated that sIL-6R up-regulates IL-6 and IL-32 expression in the acute inflammatory response to influenza A virus (IAV) infection, and IL-32 participates in a negative feedback loop that inhibits sIL-6R while upregulating IL-6 expression during IAV infection. Meanwhile, the sIL-6R exhibited extensive antiviral activity against DNA and RNA viruses via IL-27/p28 pathway, sIL-6R and p28 were physically associated and played an important role in the host antiviral response and innate immunity. As the essential IL-6/IL-12 family members, IL-6, sIL-6R, IL-27/p28 and IL-27/EBI3 could interact with each other, implying that a super interleukin 6 complex (sIL-6c) is formed in response to viral infection. Our results uncover a previously unrecognized function of IL-6 that is involved in host inflammatory response during viral infection. In this project, we will look into the mechanism by which IL-6, sIL-6R, p28 and EBI3 interacted with each other and formed a super complex with multiple experimental measures; then we will explore the functions of super IL-6 complex in host antiviral innate immune response in various virus infection systems (DNA and RNA viruses) and animal models; unveil the molecular mechanism of how the super IL-6 complex functions in innate immune signaling; and identify the inflammatory network that is mediated by super IL-6 complex (positive and negative control between different inflammatory factors). Our research work is expected to expand current knowledge about IL-6 and the way it worked during viral infection. The investigation on the functions of the super IL-6 complex will provide new insight into viral infection and host immune response.