Sirt3调节自噬与巨噬细胞分化参与分枝杆菌潜伏感染的机制研究

The formation of Mycobacterial granuloma is a typical process of antagonism between the pathogen and the host, and M2 macrophages differentiation is closely related to this course. Sirt3 is a type Ⅲ protein deacetylase which shuttles between the cytoplasm and the mitochondria. In the preliminary studies, Sirt3 deficiency was found to cause a significant reduction of M2 macrophages. Sirt3 defect also contributed to autophagy enhancement and induction of M1 macrophages. Moreover, the analysis of clinical leprosy samples showed that Sirt3 expression was gradually upregulated in the pathogenesis of M. leprae infection. It was suggested that Sirt3 may promote the differentiation and function of M2 macrophages through autophagy intervention, and participate in granuloma formation and latent infection of Mycobacterium leprae. We intend to furtherly analyze the correlation between clinical manifestations, cell typing characteristics and Mycobacterial granulomatosis formation, the cell signal transduction of Sirt3-deficient macrophage differentiation. The zebrafish model of granuloma with Mycobacterium leprae infection in vivo, will be established to reveal the effect of Sirt3 on autophagy regulation, macrophage polarization, and relevant molecular mechanisms, and to explore the mechanism of defense and compromise of immune system against Mycobacterium leprae. This study will help to clarify new mechanism for Mycobacterium immunization, providing new targets for intervention and new clues towards immune recognition as well as tolerance mechanisms.

分枝杆菌肉芽肿病理进程是典型的病原体与宿主对抗过程，M2型巨噬细胞分化与肉芽肿形成密切相关。课题组预实验发现穿梭于胞浆和线粒体定位的III型蛋白去乙酰化酶Sirt3缺陷导致M2型巨噬细胞分化与功能显著减弱、M1型巨噬细胞分化与功能显著增强，Sirt3缺陷导致自噬增强；临床患者样本分析发现Sirt3表达在麻风病程进展中逐渐增强。课题组假设Sirt3可能通过调节自噬促进M2型巨噬细胞分化与功能，参与麻风分枝杆菌肉芽肿的形成过程与潜伏感染。课题组拟进一步应用临床样本表达及细胞分型特征与麻风分枝杆菌肉芽肿进展的相关性分析、Sirt3缺陷巨噬细胞分化的细胞与信号转导、斑马鱼体内感染麻风分枝杆菌肉芽肿模型，研究Sirt3介导自噬过程调节巨噬细胞极化效应及其分子机制、探索发现机体免疫系统应对麻风分枝杆菌的对抗与妥协机制，为分枝杆菌免疫研究提供新的机制及干预靶点，也为免疫识别与耐受机制研究提供新的线索。

分枝杆菌感染仍是人类健康的严重威胁，病原体包括结核分枝杆菌、麻风分枝杆菌及非结核分枝杆菌等,其中麻风分枝杆菌感染可以导致麻风病的发生。分枝杆菌肉芽肿结构形成、演变的过程是分枝杆菌与宿主对抗的一个重要方面，也是研究分枝杆菌致病机制的重要线索。研究已知，巨噬细胞的分化与肉芽肿形成密切相关。课题组认为，Sirt3可能通过调节自噬促进M2型巨噬细胞分化与功能，参与麻风分枝杆菌肉芽肿的形成过程与潜伏感染。本课题发现了不同分型的麻风患者体内巨噬细胞的极化倾向差异；明确了Sirt3介导的巨噬细胞极化的具体作用及途径；并且探明了Sirt3与麻风分枝杆菌肉芽肿生成的因果关系。研究数据为阐明麻风分枝杆菌感染的免疫机制提供理论依据。课题成果在国内外学术期刊发表学术论文8篇,其中SCI论文5篇；培养研究生5名；课题在研期间共计参加国内外学术会议6次，并进行了8次学术报告。