血吸虫虫卵16kD钙结合蛋白诱导巨噬细胞极化调控宿主免疫病理反应的机制研究

As a major component in host innate immune system, macrophage plays important roles in anti-infection, immune regulation and repair of injured tissue. In schistosome infection, macrophage activation and polarization governs the egg granuloma initiation, development and prognosis. Schistosome 16kD calcium binding protein (SjE16.7) is a schistosome egg specific protein. Secreted by the egg, SjE16.7 recruits neutrophils and induces inflammatory hepatic granuloma initiation in schistosome infection. In primary experiments, we found that SjE16.7 induces macrophage activation and migration. Macrophage shows "alternatively activated" phenotype (M2) by treatment with SjE16.7. In this project, we plan to study the roles of SjE16.7 in M2 macrophage activation and egg granuloma development. In addition, we will study the potential roles of SjE16.7 induced M2 macrophages for allergic and autoimmune disease treatment. This study will help us better understand the pathogenesis of schistosomiasis, and find new targets for the treatment and prevention of schistosomiasis. And also, this project will help us better understand the relationship between parasites and hosts, and provide new ideas for the treatment of allergic diseases and autoimmune diseases.

巨噬细胞是机体天然免疫系统的重要组成部分，在抗感染、免疫调节与组织损伤修复中起着重要作用。在血吸虫感染中，巨噬细胞的激活分化与血吸虫虫卵肉芽肿发生、发展与转归各阶段都密切相关。血吸虫虫卵16kD钙结合蛋白（SjE16.7）是血吸虫虫卵特异性蛋白，具诱导粒细胞趋化，促进肉芽肿早期炎症反应的作用。课题组在前期研究中发现，SjE16.7可诱导小鼠巨噬细胞激活与趋化，并促进其向替代激活的巨噬细胞亚型(M2型)极化。本课题拟对SjE16.7诱导巨噬细胞极化的机制进行研究，研究SjE16.7在血吸虫虫卵肉芽肿成熟与转化中的作用。此外，本课题也将探索SjE16.7诱导巨噬细胞极化用于宿主其它免疫反应性疾病如过敏与自身免疫病治疗的潜能。这一研究将有利于我们进一步了解血吸虫的致病机制，为寻找血吸虫病防治的新靶点提供帮助。本课题也将帮助我们深入了解寄生虫与宿主的相互关系，为过敏与自身免疫性疾病的治疗提供新思路

血吸虫病是一种严重危害人类健康的寄生虫病。世界卫生组织的数据显示，全球现有2.43亿血吸虫感染者，由此引起的伤残调整生命年指数（DALY）达每年3305万。血吸虫对人体造成严重危害，主要与血吸虫虫卵沉积在宿主组织中，引起的免疫病理反应相关。SjE16.7是一种在日本血吸虫虫卵中特异性高表达的抗原，我们在以往的研究中发现，该蛋白可通过激活Rac-GTPase信号通路，显著诱导中性粒细胞激活与趋化，从而在虫卵诱导的早期炎症反应中起着重要作用。2015年起在项目的资助下，我们开始对该蛋白在巨噬细胞活化与分化中的作用进行研究。研究成果表明，SjE16.7可通过MAPK信号通路活化巨噬细胞，诱导巨噬细胞趋化与活化，活化的巨噬细胞可显著分泌IL-10与IL-12，具有类似于M2b型巨噬细胞的表型。SjE16.7激活巨噬细胞在血吸虫虫卵肉芽肿的发展与转化中发挥重要作用，封闭该因子，可显著减轻相关病理反应，提示具有成为血吸虫病治疗靶点的应用前景。在对SjE16.7诱导巨噬细胞活化所需受体及细胞内信号通路相关研究中，我们证实SjE16.7可与细胞表面的RAGE受体结合，诱导细胞内ROS的产生与NKkb信号通路活化，这一过程与体内髓系来源抑制细胞诱导与积累相关，有着免疫负调控的作用。该机制可能是SjE16.7调节自身免疫病等免疫病性疾病与促进血吸虫相关肿瘤发生的原因。