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

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.

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。

清道夫受体A（SRA）是天然免疫中一个重要的模式识别受体，参与多种生理和病理过程。我们前期发现SRA在乙肝患者肝组织及血清中高表达，提示SRA可能参与HBV感染的免疫调控。在本研究项目中，我们重点关注SRA对抗肝炎病毒免疫应答的调控作用，从体外细胞学实验及动物模型实验，分析SRA对乙肝免疫发病机制的调控作用，以期为基于SRA为靶点的病毒肝炎治疗研究提供依据。主要的研究结果有：(1)用小鼠肝炎病毒MHV-A59诱导小鼠急性重症肝炎，模拟HBV急性感染导致的肝炎症状。研究发现：SRA基因缺陷小鼠较野生型WT小鼠死亡率降低，肝组织损伤明显减轻。机制研究发现：SRA通过促进MHV-A59刺激中性粒细胞内TAK1磷酸化上调ERK的激活进而影响中性粒细胞胞外诱捕网（NET）的形成，进而促进C5a的生成，加重小鼠肝炎症状。(2)SRA可通过与TRAF3直接结合，抑制TRAF3泛素化，最终导致I型干扰素应答降低，进而抑制抗HBV病毒应答效应。(3) SRA抑制剂褐藻糖胶可以抑制HepG2.2.15细胞内HBcAg的表达以及HBsAg、HBeAg、和HBV DNA的分泌，动物学实验结果表明，褐藻糖胶可有效地缓解pHBV1.3质粒诱导急性HBV感染模型及MHV-A59感染所致急性重症肝炎的小鼠肝脏损伤。综上，SRA负向调控机体抗HBV免疫应答，其抑制剂褐藻糖胶可缓解肝病病毒感染所诱发的肝损伤。此外，在本项目的资助下，我们研究了另一重要的模式识别受体甘露聚糖结合凝集素(MBL)对药物性和化学性肝组织损伤的调控作用，分析其对免疫细胞活化的调节作用；我们还研究了n-3不饱和脂肪酸 (n-3 PUFAs) 对免疫性肝损伤和药物性肝损伤的调控作用。项目基本完成既定研究目标，在Journal of Hepatology、FEBS Journal和FASEB Journal等杂志发表SCI论文10篇，已培养毕业研究生5名。

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