单核细胞趋化蛋白诱导蛋白1在病毒性心肌炎中的免疫调节(和抗病毒)作用及其机制研究

Viral myocarditis has been recognized as nonspecific inflammations of cardiac muscle caused by virus infection, especially by Coxsackievirus group B type3. Currently, the role of immune response by innate immune cell is considered more important than the direct damage by virus. Thus, searching for immune molecular with the antiviral effects and down-regulation of immune response will be promising. MCP-1-induced protein-1 (MCPIP1) is a newly identified CCCH zinc finger protein that is induced in human monocyte-derived macrophages when stimulated by monocyte chemotactic protein (MCP-1) or IL-1β. As an essential RNase, MCPIP1 plays a key role in the down-regulation of inflammatory cytokines such as IL-6 and IL-12p40 and also exhibits broad-spectrum antiviral effects such as dengue virus and HIV. In this study, we will investigate the function of MCPIP1 in CVB3-induced virus myocarditis and its underlying mechanism. We plan to use PEI-plasmid mediated knockdown mice and adenovirus-infected macrophages adoptive injected overexpression mice to explore the effect of MCPIP1 in VMC progress and pathologic injury and to ascertain the role of inflammation regulation and virus replication of MCPIP1. Based on above, we will further study the molecular mechanism of MCPIP1 in regulating CVB3 replication and innate immune response in vitro. This work will clarify the potential role of MCPIP1 in the pathogenesis of VMC and provide a new therapeutic idea for VMC immune therapy.

病毒性心肌炎（VMC）属于感染性心肌病，B3型柯萨奇病毒（CVB3）感染是主要病因之一，其发病机制尚不完全清楚。已发现免疫细胞分泌的炎症因子是心肌炎症加剧的主要原因，故寻找炎症调控新分子是研究的热点。MCPIP1作为新型RNA酶可下调炎性因子的分泌，也可抑制某些RNA病毒的复制。我们过去研究发现该分子可识别某些细胞因子mRNA 3’UTR上的茎环结构使其降解进而负向调控免疫应答。本课题拟重点研究MCPIP1对VMC炎症的免疫调节和抗病毒作用及其机制。通过对VMC小鼠体内干扰和过表达MCPIP1，分析其对VMC发病、病毒复制及炎症的影响；深入探讨MCPIP1对炎性细胞因子的分泌及对病毒复制的调控是否与其RNase活性介导的转录后调控相关；探讨蛋白酶体抑制剂能否通过提高MCPIP1表达进而控制VMC进展。本课题可能为VMC发病的炎症机制提供新的补充，并提出以MCPIP1为靶点的新型免疫治疗策略

单核细胞趋化蛋白诱导蛋白1(MCPIP1)是一种重要的炎症免疫调控分子，其可作为RNA酶或去泛素化酶负向调控免疫应答过程。新近发现，其还可以直接与某些特定病毒的RNA相互作用直接降解后发挥抗病毒效果，包括日本脑膜炎病毒、登革热病毒等。然而其在B3型柯萨奇病毒（CVB3,单股正链RNA病毒）感染过程中的作用至今未见报道。通过我们的实验发现：当CVB3感染原代心肌细胞和小鼠时，心肌细胞及小鼠心脏、胰腺组织中MCPIP1的mRNA和蛋白水平均明显上调表达。进一步研究发现过表达MCPIP1可抑制CVB3的复制，干扰MCPIP1表达可促进病毒复制。荧光素报告基因分析发现MCPIP1通过靶向CVB3 3’UTR降解病毒RNA且该作用依赖于其RNA酶活性而非去泛素化酶的功能。此外，我们证实了MCPIP1可以在CVB3诱发巨噬细胞的炎症反应中起到负向调控作用。因此，我们结果表明MCPIP1可作为有效的宿主防御分子抑制CVB3复制并可抑制其介导的固有免疫炎症。