CypA调节流感病毒感染引发细胞因子风暴的分子机制研究

Factors implicated in influenza A virus-induced inflammatory response include robust cytokine production (cytokine storm), excessive inflammatory infiltrates, and virus induced tissue destruction. Excessive inflammatory response could lead to death. In our previous study, upon influenza virus A/WSN/33 infection, IL-6 and MCP-1 were decreased in the serum of CypA over-expressed mice compared with wild-type animals. In addition, both the inflammation reaction and the lung injury were reduced in CypA over-expressed mice. In the present study, firstly, we will detect the physiological indices, tissue destruction and the levels of cytokines in influenza virus infected CypA knock-out (CypA-/-), CypA over-expressed and wild type mice. In addition, we will use RNA sequencing to profile the host transcriptional response to the viral infection in CypA-/-, CypA over-expressed and wild type mice so as to determine how CypA regulates the formation of cytokine storm and further to find the interacted host factors related with IL-6 and MCP-1. Finally, we will focus on the mechanism of CypA regulating the IL-6 and MCP-1 related signal pathway and then illuminate the mechanism of CypA regulates cytokine storm during influenza virus infection, so as to recognize the mechanism of the occurrence and development of inflammation from different points of view and provide an enlightening insight to anti-inflammatory drug research and development

流感病毒感染导致的炎症反应主要是由大量细胞因子的产生、炎性浸润以及病毒诱导的组织损伤引起，过度的炎症反应最终可导致死亡。前期小鼠实验结果表明，流感病毒A/WSN/33感染后，CypA下调血清中IL-6、MCP-1等细胞因子的表达水平，并且减轻肺组织的病理损伤。本项目拟在前期基础上，研究CypA敲除及高表达小鼠对于流感病毒感染后的炎症反应及组织损伤情况，进一步探讨CypA在炎症反应过程中对于细胞因子风暴形成的调控机理；同时运用RNA sequencing技术分析病毒感染后小鼠肺部组织的转录图谱变化，确定CypA是如何在分子水平影响细胞因子风暴的形成，寻找与IL-6、MCP-1等相关信号通路相互作用的宿主因子；进一步在细胞水平研究CypA参与信号通路的作用机制，从而阐明CypA调节流感病毒感染所引发细胞因子风暴的分子机制，以不同的视角认识炎症反应发生发展的分子机制，为抗炎药物的研发提供新思路。

流感病毒感染可引起细胞因子风暴、炎性细胞浸润及组织损伤，过度的炎症反应最终可导致死亡。本研究利用流感病毒A/WSN/33感染CypA转基因小鼠的动物模型，探索了CypA调节流感病毒感染引发细胞因子风暴的分子机制。发现CypA转基因小鼠能够抑制流感病毒感染引起的炎症反应及组织损伤；病毒感染后，CypA转基因小鼠腹腔巨噬细胞中上调基因涉及的功能有细胞迁移、免疫、器官发育等，下调基因涉及免疫细胞的正向调控基因和自噬相关基因；CypA能够与p65相互作用，下调TLR3/7介导的NF-κB信号通路。本研究初步阐明了CypA调节流感病毒感染引发细胞因子风暴的分子机制，表明CypA是流感病毒感染引发细胞因子风暴的重要调节因子。