C5a/C5aR信号对CD4+ T细胞防御隐孢子虫感染的调节作用及机制

解析宿主抗隐孢子虫免疫机制是防控其感染的根本途径。已明确CD4+ T细胞中Th1、Th2和Th17是宿主抗隐孢子虫感染关键细胞亚群，但其抗感染效应调控机制尚不清楚。C5a/C5aR信号对病原特异CD4+ T细胞及其亚群产生和效应有重要调节作用，我们前期研究发现微小隐孢子虫感染鼠脾脏和小肠C5a及受体C5aR显著上调表达，且与IL-17和IFN-γ消长相关联。据此我们认为C5a/C5aR信号对隐孢子虫特异CD4+ T细胞效应有调节作用。本项目拟以微小隐孢子虫为对象，以小鼠和猪肠上皮细胞为模型，采用细胞和分子手段，探讨该信号对隐孢子虫致病性的影响，研究其对隐孢子虫诱发树突状细胞成熟及对CD4+ T细胞活化共刺激分子表达、细胞亚群分化和效应的作用，最终从体内外系统阐明C5a/C5aR信号调节CD4+ T细胞抗隐孢子虫感染的作用机制，为防控隐孢子虫病药靶和疫苗候选基因筛选提供新思路。

Analyzing the immunological mechanism of host against Cryptosporidium infection is the fundamental way to control cryptosporidiosis. Previous studies have indicated that Th1, Th2 and Th17 cells were key subsets to resolve Cryptosporidium infection, but the immunological mechanism of anti-infection effect has not been clearly stated. The C5a/C5aR signal has been suggested to have important role to regulate stimulation and effect of CD4+ T cells and its subsets. Our previous study found significantly up-regulated expression of C5a and C5aR in spleen and small intestine during C. parvum infection and association between this change and dynamics of IL-17 and IFN-gamma. Therefore, we assume that the C5a/C5aR signal has regulative role to Cryptosporidium specific CD4+ T cell effect. To address this hypothesis, this project will investigate the effect of C5a/C5aR signal to pathogenicity of C. parvum, maturation of dendritic cells induced by C. parvum, expression of activation costimulatory molecules of CD4+ T cells, and differentiation and response of CD4+ T cell subsets, using C. parvum, models of mice and swine intestine epithelial cells, and cellular and molecular technologies. The findings of this project will systematically clarify the regulative role and its mechanism of C5a/C5aR signal to CD4+ T cells against Cryptosporidium infection in vivo and in vitro, and shed new light to screen new effective drug targets and vaccine candidate genes to control cryptosporidiosis.