DUSP5介导的脂代谢在巨噬细胞抗结核分枝杆菌感染中的作用及其机制研究

结核病是由结核分枝杆菌（Mtb）感染引起的，该病的流行给人类健康带来严重威胁。肺泡巨噬细胞是Mtb感染的靶细胞，也是机体抗Mtb感染免疫的主要效应细胞，在抗结核免疫中发挥重要作用。双特异性磷酸酶（DUSPs）蛋白家族成员已被证实参与了很多与脂代谢有关的代谢紊乱疾病的调节，我们前期的研究结果发现，DUSP5能通过ERK1/2途径调节Mtb感染后诱导的巨噬细胞自噬，并参与调控巨噬细胞脂代谢的过程。本研究拟在前期工作的基础上，建立DUSP5过表达/干扰巨噬细胞模型和小鼠肺脏感染模型，分析Mtb感染引起的脂代谢的变化，探究DUSP5对肺组织清除Mtb的影响以及对肺组织抗Mtb感染免疫的调控作用，阐明其分子机制。这将为基于改变宿主细胞代谢途径，促进宿主细胞免疫清除能力的抗结核免疫研究提供新的研究方向和思路，也有助于探讨免疫代谢调控宿主-病原相互作用及Mtb如何逃逸免疫细胞的监视和杀灭等机制的阐明。

Tuberculosis (TB), caused by the infection of Mycobacterium tuberculosis (Mtb), is one of the world’s leading infectious diseases and major public health problem. Alveolar macrophages are believed to be among the first cells to phagocytose, contain and kill Mtb, and also the main effector cells of immunity against Mtb infection. They play important roles in the host defense against Mtb infection. Some of the dual-specificity phosphatases (DUSPs) family members have been confirmed to be involved in the regulation of many lipid metabolic disorder related diseases. Our recent study has revealed that DUSP5, one of the members of DUSPs plays an important role in regulation of the macrophage RAW264.7 cells autophagy induced by Mtb infection through extracellular signal-regulated kinases (ERK1/2) pathway, and participates in the regulation of macrophage lipid metabolism. Therefore, on the basis of our previous work, this study intends to establish the overexpression/interference cell models of RAW264.7 and the murine model of lung infection to explore the effects of DUSP5-mediated lipid metabolism in macrophage defense against Mtb and clarify its molecular mechanism. Hopefully, this study will lay a foundation for fully understanding the immunometabolism of macrophages induced by Mtb infection as well as the mechanisms of anti-TB immunity and molecular pathogenesis of Mtb.