Ipr1蛋白抗结核的机理研究

Tuberculosis (TB) is a chronic and infectious disease caused by Mycobacterium tuberculosis (MTB). As a zoonosis, TB strongly threatens human heath worldwide and caused severely economic loss to cattle industries. About 1/3 of the human population were infected with MTB, however, only 1/10 infectants develop to active pulmonary tuberculosis, indicating that the hereditary factors are essential for host resistance to TB. Located on the chromosome 1 of mouse, Ipr1 have been proved to inhibit multiplication of intracellular pathogens such as MTB and Listeria monocytogenes, and to switch the apoptotic pathways of infected macrophages. The closest homologue of Ipr1 in human is SP110, genetic polymorphisms of SP110 are associated with TB susceptibility in human and holstein-friesian cattle. These results suggested that Ipr1 is a pivotal gene for host resistance to TB, and elucidation of the mechanisms of Ipr1-mediated resistance to MTB is significance for prevention and treatment of tuberculosis, as well as disease-resistant animal breeding. However, to date, the mechanism of Ipr1-mediated resistance to MTB is unclear. In this study, we intend to investigate the mechanism of Ipr1 function by analyzing Ipr1 protein interactome and the gene expression profile of Ipr1 overexpressing macrophages, the results will provide theoretical and practical basis for breeding of anti-TB livestocks.

结核病是由结核分枝杆菌引起的慢性传染性疾病，该病为人兽共患病，对人类健康造成严重威胁，也给养牛业造成严重的经济损失。全球约三分之一的人感染结核分枝杆菌，但仅有约十分之一的感染者发展成活化肺结核，说明遗传因素对机体抗结核具有重要影响。位于小鼠1 号染色体上的 Ipr1 基因被证明能抑制结核分枝杆菌和李斯特菌等胞内寄生菌增殖，并将感染的巨噬细胞从坏死转变为凋亡。Ipr1的人类同源基因SP110遗传多态性与结核易感性相关。这些结果表明 Ipr1是宿主细胞抗结核的重要基因，阐明其抗结核的分子机制对于结核病的防治和抗病动物育种具有重要意义。但是，迄今为止，Ipr1介导巨噬细胞抗结核的机理尚不清楚。本项目拟从 Ipr1相互作用蛋白及其调控的基因入手研究 Ipr1 介导巨噬细胞抗结核的机理，研究结果将为家畜抗结核病育种提供理论和实践依据。

结核病是由结核分支杆菌引起的慢性人兽共患传染病，全球每年仅因牛结核病造成的经济损失约占养牛业收入的10%以上，同时有约15%的结核病病人是由结核病牛直接或间接传染，严重威胁着我国奶牛养殖业的可持续发展及人类公共卫生安全。结核分支杆菌可以通过多种毒力因子抑制巨噬细胞的直接杀伤作用、活化和凋亡等作用以实现免疫逃逸。同时宿主对于结核分支杆菌的抵抗力受到多基因联合影响，存在典型的遗传背景差异。本研究对巨噬细胞内Ipr1基因的蛋白组、转录组和表观组进行联合分析，通过构建IPR1互作蛋白网络并对新挖掘的关键互作蛋白作用机理进行研究，阐明了结核分支杆菌感染后STAT1磷酸化上调IPR1及促炎基因表达后，IPR1一方面通过 KF-κB和p53通路促进细胞凋亡，另一方面IPR1与Hspa5等内质网胁迫标记蛋白互作影响内质网应激，IPR1互作蛋白BAG2进一步激活内质网自噬和细胞自噬的胞内信号通路。揭示了Ipr1增强先天免疫细胞清除胞内寄生的结核分支杆菌能力的分子机制，为家畜抗结核病育种提供了理论依据与实践基础。