线虫半胱氨酸蛋白酶抑制因子免疫调控的分子机理

Nematode parasite infections are very common in many parts of the world. In addition to causing phathological injuries, these pathogens also induce immunosuppression in the host. Several immunomodulators have been identified in nematode parasites, and recent studies show that the cysteine proteases inhibitor (CPI) is one of the major immunomodulators produced by nematode parasite. We have demonstrated that the recombinant CPIs from murine nematode Heligmosomoides polygyrus (Hp-CPI) and human nematode Ascaris lumbricoides (Al-CPI) modulate the differentiation and antigen presentation function of DCs. However, the molecular mechanisms underlying the modulatory function of CPI are not fully characterized. We hypothesize that nematode CPIs modulate immune cell functions by inhibition of cysteine proteases that are involved in a number of important molecular events in the immune cells. In this proposed study, we will investigate the effects of Hp-CPI and Al-CPI on a number of molecular events, including antigen procession, step-wise cleavage of the chaperon protein invariable chain (Ii), MHC-II-Ag complex presentation on cell surface and the intracellular cleavage and activation of TLR receptors in dendritic cells, the important antigen-presenting cells. The results from this study will provide insight into the molecular mechanisms of parasite evasion of host immunity. The immunoregulatory features of parasite CPI can be further exploited for development of drugs for autoimmune diseases treatment or tissue transplantation.

目前已知，线虫寄生虫感染可造成宿主直接病理损伤，还可诱导显著的免疫抑制。在已知的多种线虫免疫调控物质中，半胱氨酸蛋白酶抑制因子（CPI）是一重要免疫调控分子。我们研究发现，来自小鼠螺旋线虫和人蛔虫的重组CPI可抑制宿主抗原递呈细胞（APC）的成熟活化及激活CD4+ T细胞的能力，从而诱导免疫抑制，但是，目前CPI在免疫细胞内的作用机制及其靶分子尚不清楚。我们推测，CPI可能是通过干扰APC细胞内众多依赖半胱氨酸蛋白酶的分子功能发挥免疫调控/抑制作用的,前期结果已部分证实此假说。本课题将系统研究线虫CPI对APC内蛋白抗原的酶切降解处理、MHC-II分子伴侣蛋白（Ii链）分步剪切和MHC-II-抗原复合物表面递呈、Toll样受体胞内酶切降解和活化等重要过程的影响，阐明线虫免疫调控分子对宿主免疫调控作用的机制。研究结果有望揭示线虫免疫逃逸的分子机理，并为新型抗自身免疫病的药物研发提供理论依据。

本研究项目的主要目标是从分子水平揭示线虫半胱氨酸蛋白酶抑制因子（CPI）对抗原递呈细胞的抗原递呈和TLR信号通路的抑制作用，以此揭示线虫诱导宿主免疫抑制的机理。目前我们已完成CPI分子对树突状细胞摄取和递呈抗原的干扰及CPI对树突状细胞MHC-II 分子伴侣Ii链的抑制作用等工作。在构建TLR9-flag的BMDC细胞系方面遇到一些技术困难。目前我们拟采用其他途径和方法解决该问题，并回答CPI分子是否对TLR9受体胞内信号传递过程是否有作用这个问题。与此项目相关的工作是解析线虫CPI蛋白分子的结构与功能的关系。与我院其他研究组合作，我们已分析确了线虫CPI分子的功能结构域。该项工作已于2014年发表。