SRA通过TRAF3调控MDA5/RIG-I信号通路的活化及其在抗HBV免疫应答中的意义

本课题组曾报道清道夫受体A（SRA）在乙肝患者体内高表达并调控抗HBV特异性T细胞应答。最近我们发现SRA能与TRAF3结合且HBV感染时二者结合力增强，而TRAF3是MDA5/RIG-I等信号通路中的关键接头分子，且MDA5/RIG-I通路在机体抗HBV天然免疫应答中起重要作用。本项目拟研究：①SRA对HBV感染肝细胞激活天然免疫信号通路的调控作用；②SRA与TRAF3相互作用的分子基础及前者对后者功能的影响；③SRA对kupffer细胞MDA5/RIG-I通路活化诱导抗HBV免疫应答的调控作用；④SRA抑制剂褐藻糖胶对MDA5/RIG-I通路及乙肝进程的影响。从而阐明SRA调控MDA5/RIG-I通路的机制及其在抗HBV免疫应答中的意义，揭示SRA抑制剂对HBV感染的影响及机制，将丰富对SRA参与抗病毒天然免疫应答的认识，并为发展基于SRA为靶点的乙肝免疫治疗新策略提供理论和实验依据。

Our group previously demonstrated that the level of scavenger receptor A (SRA) was highly elevated in patients with chronic type B hepatitis and SRA could suppress HBV specific CD8+ T cell responses. We recently observed that SRA interacted directly with TRAF3, an important adaptor protein for MDA5/RIG-I and other innate immunity pathways. The interaction between SRA and TRAF3 was enhanced upon HBV infection. It has been reported that MDA5/RIG-I pathway plays a crucial role in the initiation of host innate immune response against hepatitis B virus (HBV). Thus, the specific aims of this proposal are to: ① Elucidate the regulatory function of SRA in HBV elicited innate immune responses in infected hepatocytes. ② Demonstrate the precise molecular mechanism about the interaction between SRA and TRAF3. Evaluate the influence of SRA in TRAF3 function. ③ Determine the immune regulatory role of SRA in kupffer cell producing interferon (IFN), which mediated anti-HBV immune response, induced by RIG-I and MDA-5 signaling pathway. ④ Explore the potential regulatory function of fucoidan, a well-known SRA agonist, in MDA5/RIG-I signaling pathway and elucidate its role in immune responses against HBV infection. . The project will define the role of SRA in the pathogenesis of HBV infection and its regulatory function in host MDA5/RIG-I immune response against HBV infection. In addition, it will provide a new understanding about SRA that it participates in anti-viral innate immune response and the precise mechanism. These studies are expected to help identify new potential target for immunotherapy of chronic hepatitis B virus infection.