Wip1在金黄色葡萄球菌肺炎固有免疫防御中的作用及机制研究

The incidence of lung infection and lung injury is high in the world, and Staphylococcus aureus infection is one of the main causes of severe lung inflammation. Our previous study found that the loss of Wip1 (wild-type p53-induced phosphatase) can cause a remarkably increase in lung inflammation caused by Staphylococcus aureus infection, and enhance the inflammatory response of macrophages and increase bacterial clearance, and Wip1 regulates the number of mitochondria. Mitochondria play an important role in host cell defense against bacterial infection. This project will focus on the effect of Wip1 protein on mitochondrial homeostasis and its related functions in macrophages, to explore whether Wip1 exerts immunoregulatory functions by affecting the PGC-1α-TFEB axis and clarify Wip1 innate immune response and molecular mechanisms at a deeper level. Establish an intrinsic link between this molecular function and lung immune-inflammation-injury.

肺部感染及其所导致的肺损伤在世界范围内发病率处于较高水平，而金黄色葡萄球菌（Staphylococcus aureus）的感染是导致严重肺部炎症发生的主要原因之一。我们前期研究发现Wip1(wild-type p53-induced phosphatase 1)基因的缺失可致小鼠由金葡菌感染引发的肺部炎症显著增加，并增强巨噬细胞的炎症反应及清除细菌的能力，且Wip1能调控线粒体的数目。在宿主细胞防御细菌感染中线粒体起着重要作用。本项目将聚焦于Wip1蛋白对于巨噬细胞线粒体稳态及其相关功能的影响，着重探讨Wip1是否通过影响PGC-1α-TFEB轴而发挥免疫调控功能，拟从更深刻的层次上阐明Wip1在固有免疫应答及免疫反应中的作用及其分子机制, 建立该分子功能与肺部免疫-炎症-损伤之间的内在联系。

细菌性感染导致的肺损伤及严重性肺炎是危害人类健康的常见临床疾病，人们对其发生机制目前仍未完全了解。本项目利用小鼠细菌性肺炎模型及细菌感染细胞模型，探索了蛋白磷酸酶Wip1在调控巨噬细胞线粒体稳态及免疫应答中的功能。结果发现Wip1通过抑制SA诱导的线粒体自噬促进异体自噬，增强巨噬细胞功能；进一步明确了TFEB是关键的调控分子，协调着自噬-线粒体免疫代谢。为阐明Wip1在感染-炎症-免疫代谢的生物学功能及其调控机制提供新线索，为抗感染治疗提供了新思路。