中东呼吸综合征冠状病毒免疫病理损伤致病机制研究

The Middle East respiratory syndrome coronavirus is a highly pathogenic coronavirus(MERS-CoV) emerged in the Middle East in 2012, its mortality rate as high as 35%, far higher than the SARS virus (8-10%). Once the outbreak or epidemic will cause a great threat to the health of the population. To date, lack of systematic studies on the mechanism of immune pathogenesis of the virus infection, especially on the mechanism of the “storm of inflammatory cytokines” and complement mediated immune pathogenesis of the virus infection. In this study, In this study, we will use the Human DPP4 transgenic mice model with MERS-CoV infection and analyze the charachateristic hispathology of MERS-CoV infection, and clarify the roles of cytokines storm and the abberent complement activation in the immunopathogenesis of MERS-CoV infection. This study will also explore new treatment strategy to decrease the inflammatory responses and deduce the tissue damages by blocking or inhibiting excessive activation of complement. Through this study, we will reveal the roles of Inflammatory cytokines storm, and abberent complement activation in pathogenesis of MERS-CoV infection.

中东呼吸综合征冠状病毒是2012年在中东地区新出现的一种高致病冠状病毒，其致死率高达35%，远高于SARS病毒（8-10%）。目前在中东地区高发。该病毒具有传播扩散的危险性，人群普遍易感，一旦暴发或流行将会对人群健康造成巨大威胁。迄今，国内外均缺乏对该病毒感染免疫病理损伤机制的系统研究，尤其对炎症因子风暴发生的机制、补体介导的免疫病理损伤作用等均没有进行深入研究，也缺乏针对免疫致病靶标的免疫治疗的探索研究。针对上述存在的问题，本研究利用课题组建立成功的人DDP4转基因小鼠模型,结合分子生物学和分子免疫学实验，从分子水平、细胞学和动物实验等不同水平，探索该病毒导致的“炎症因子风暴”发生的机制及补体介导的免疫病理损伤作用和机制等，系统研究该病毒所致免疫病理损伤作用及机制；同时探索以靶向补体抑制为基础的免疫治疗作用和效果，为临床免疫治疗提供理论基础。

本研究通过转基因技术成功构建了hDPP4转基因小鼠，并利用该小鼠建立了MERS-CoV致死性感染模型。该模型能较好的模拟临床感染状态，在MERS-CoV 致病机制与药物疫苗评价中发挥重要作用。MERS-CoV感染hDPP4转基因小鼠后会引起宿主补体过度激活和异常的免疫反应，用抗C5aR抗体阻断C5a-C5aR补体途径后能显著降低异常的免疫反应，有效减轻过度免疫反应造成的免疫组织病理损伤。本研究揭示了MERS-CoV感染所致组织损伤新机制，为MERS-CoV感染的防治提供了一条新的免疫干预治疗策略.