CD157调控巨噬细胞功能增强宿主抗结核免疫的作用机制

The result of infected of mycobacterium tuberculosis (MTB) depends on the host immunity, however, the mechanism of host immunity against mycobacterium tuberculosis still not clear. Our previously data showed that CD157 highly expressed in macrophages in the blood from patients with TB, and the level of CD157 expression was highly related with the occurrence and development of TB. What was more, the CFU was higher in CD157 knockout mouse as well as pathology was more serious comparing with WT mouse. It showed that CD157 could enhance the host immunity against MTB. But it is not clear that how CD157 enhanced the host immunity. In vitro, we found that CD157 could enhance the bactericidal ability and the function of secreting inflammatory cytokines of macrophage. Based on these results, we hypotheses that CD157 could enhance the host innate and acquired immunity against MTB by enhancing the ability of bactericidal and secreting cytokines of macrophage. The project will further study the mechanism of CD157 enhanced the ability of bactericide and inflammatory cytokines expression of macrophage. After then we could explore the impact and mechanism of CD157 regulated T cell immunity by controlled the function of macrophage. This project is expected to reveal the mechanism of CD157 regulating tuberculosis immunity and provide a theory for CD157 as a target for host directed therapy.

宿主抗结核免疫是决定结核感染是否发病的关键，但其调控机制尚不清楚。我们前期发现结核患者单核巨噬细胞CD157高表达，CD157表达水平与结核病发生发展密切相关。与野生型小鼠相比，CD157基因敲除小鼠肺部结核菌含量显著增多，病理损害显著加重，表明CD157具有增强宿主抗结核免疫的作用。那么，CD157增强宿主抗结核免疫的具体机制如何？体外结核感染模型证实，CD157可以直接增强巨噬细胞清除结核菌的能力，并上调巨噬细胞炎症因子的分泌。据此，我们提出假说：CD157通过增强巨噬细胞杀菌和炎症因子分泌能力，从而增强宿主固有和获得性抗结核免疫。本项目围绕上述假说，进一步阐明CD157增强巨噬细胞直接杀菌能力和炎症因子表达的具体机制，探讨CD157调控巨噬细胞功能对于T细胞免疫的影响和机制，深入揭示CD157调控宿主抗结核免疫的机制，为基于宿主基因定向治疗结核病策略提供潜在新靶点和科学依据。

结核病是当前严重危害人类健康的重大传染病。寻找结核病，尤其是耐多药结核的治疗新策略是临床的迫切需求。宿主抗结核免疫是决定结核感染是否发病的关键，因此阐明其调控机制和通路是研发基于宿主基因定向治疗结核病的新策略（host directed therapy, HDT）的关键。. 在感染部位招募单核细胞是宿主对结核分枝杆菌耐药的关键。CD157在中性粒细胞和单核细胞穿过内皮细胞迁移和粘附中起关键作用，但其在结核病(TB)中的作用尚不清楚。通过本研究，我们发现Cd157的mRNA和蛋白水平在结核分枝杆菌感染期间显著升高。在小鼠结核模型中，Cd157缺失通过增加细菌负担和肺部炎症损害宿主对结核分枝杆菌感染的反应。体外实验表明，Cd157敲除(KO)巨噬细胞的杀菌能力降低，这是由于结核菌诱导的活性氧(ROS)产生受损。我们进一步揭示，CD157与TLR2和PKCzeta相互作用，促进结核菌诱导的CD157 KO巨噬细胞产生ROS，从而增强结核菌的杀伤能力。在临床方面，我们观察到有效的抗结核化疗后CD157的表达下降。与肺炎和肺癌患者相比，结核性胸膜炎患者的胸液中CD157明显升高。有趣的是，可溶性CD157 (sCD157)的水平与人外周血单核细胞来源的巨噬细胞杀菌活性相关。外源性施用sCD157可弥补巨噬细胞的杀菌能力，恢复活性氧的产生。总之，我们已经发现了CD157在结核分枝杆菌感染过程中通过TRL2依赖性ROS产生的一种新的保护性免疫功能。应用sCD157可能是一种有效的策略，用于靶向治疗那些缺乏CD157产生的结核病。. 本项目通过阐明 CD157 增强宿主抗结核免疫的具体机制和通路，为靶向 CD157 的HDT 可行性提供科学依据。项目完成对于结核病，尤其是耐多药结核的治疗具有重要意义。