清道夫受体A参与抗HBV感染的机制研究

Although it is recognized that the effective innate and adaptive immune responses are crucial for viral clearance as well as pathogenesis during HBV infection, the precise mechanisms contributing to failure of HBV eradication and the autoimmune-associated liver injury are poorly defined. We recently discovered that class A scavenger receptor SRA acts as an intrinsic immunosuppressive molecule during a pathogen-induced inflammatory response and antitumor immunity. We also made observations that the SRA/CD204 expression is highly elevated in chronic HBV patients. In addition, upregulation of SRA/CD204 on hepatic myeloid cells or significant increase of soluble SRA/CD204 result in profound inhibition of T cell activation in an experimental hepatitis model. This leads us to investigate whether scavenger receptor family members have unique roles in modulation of immune-mediated controlling of HBV infection and immunopathology. Our main hypothesis is that the SRA/CD204 dampens virus-specific effector cell functions, therefore negatively regulating viral control during HBV infection. The objective of this US-China Research Program is to initiate the collaborative research to study the immunoregulatory functions of SRA/CD204 in liver diseases triggered by viral infections. The project builds on existing scientific capacity for broad preclinical and clinical research at both institutions, and aims to determine the involvement of SRA/CD204 and the mechanisms of its action in regulating the quality and magnitude of antiviral cellular immunity as well as associated immunopathology. These studies are expected to provide a better understanding of the functional significance of SRA/CD204 in human disease pathogenesis during HBV infection and help identify new potential targets for intervention. The successful completion of this project will have important implications for developing novel immunomodulating treatment modalities or vaccine therapy for human chronic viral infections as well as other diseases (e.g., cancer and autoimmune disorder).

在HBV 感染的病毒清除过程中，细胞免疫起着重要作用，但其所引发的免疫应答也成为肝损伤的发病机制。确定增强HBV病毒消除同时减少免疫反应导致组织损伤的治疗策略是乙肝研究的重中之重。前期研究表明清道夫受体A（SRA）在病原体引起的炎症反应和抗肿瘤细胞免疫反应中发挥免疫抑制功能，进一步发现乙肝患者肝组织及血清中高表达SRA 并且可溶型SRA可抑制T 细胞的活化，这一结果提示SRA 可能参与HBV 感染进程的调控。本项目拟通过研究SRA 对HBV 感染过程中的抗病毒免疫及组织损伤的调节，确定SRA 在HBV抗原特异性CTL效应中的意义。该项目是建立在广泛的基础实验和临床研究基础上的，研究结果深化对HBV 感染免疫学发病机制的认识，并为慢性乙型肝炎的临床免疫学治疗提供新的靶点，也为开发人类慢性病毒感染及其他疾病（如癌症和自身免疫性疾病）的免疫治疗方案提供理论依据。

在HBV感染的病毒清除过程中，细胞免疫起着重要作用。研究表明清道夫受体A(SRA)在抗肿瘤细胞免疫反应中发挥免疫抑制功能。我们在研究中发现乙肝患者肝组织及血清中高表达SRA并且可溶型SRA可抑制T细胞的活化。本项目拟通过研究SRA 对HBV感染过程中的抗病毒免疫的调节确定SRA 在HBV抗原特异性CTL效应中的意义，进行了下述研究：① HBV感染不同阶段及治疗病人血清中SRA的表达规律，可溶性SRA对HBV特异性CTL应答的调节；② 分析SRA对HBV感染诱导HepG2细胞因子分泌及信号转导的调节；③SRA在小鼠暴发性病毒肝炎中的免疫调节作用。该项目包含基础实验和临床研究两方面的研究工作，现有研究结果表明：①HBV慢性感染后，患者血清中可溶性SRA的分泌量会升高；乙肝患者经替比夫定治疗后，血清SRA水平显著下降。可溶性SRA抑制TCR信号通路从而负向调控HBV特异性CTL应答的调节；②SRA下调HBV病毒感染HepG2细胞诱导的细胞因子应答；③ SRA加剧鼠肝炎病毒株MHV-A59导致的小鼠肝组织病变，研究表明SRA可能通过调控凝血酶原FGL2影响MHV-A59感染进程。本项目研究结果初步阐明了SRA参与HBV感染进程并调控病毒特异性免疫学应答，研究结果深化对HBV 感染免疫学发病机制的认识，为下一步开展基于SRA为靶点的乙肝免疫调控及临床免疫学治疗研究提供了坚实的基础。. 截止目前，与本项目研究直接相关的研究结果已发表中文核心期刊文章一篇（陈莺等，热带医学杂志，2014）并且另有一部分工作已投稿BMC Immunology，杂志修回意见积极，现正在补充实验。此外，基金资助的一个工作于2014年3月发表在FEBS Letters杂志（Liu H, et al. FEBS Lett. 2014）。