内质网应激诱导的caspase-1激活对牛分枝杆菌存活的影响机制

Tuberculosis (TB) is a zoonotic disease that has an important global impact and is caused by mycobacterium tuberculosis complex, including mycobacterium bovis (M.bovis). IL-1β secretion can be induced by M.bovis after infecting and entering macrophage. A recent study reported that caspase-1, activated by the inflammasome formation, was involved in the regulation of IFN-β by direct cleavage of dsDNA sensor cGAS. Our previous study has shown that endoplasmic reticulum stress (ERS) in macrophages induced by M. bovis infection can significantly improve the secretion of IL - 1β, but how does ERS induce inflammasome formation and activate caspase-1? Whether the activated caspase-1 participate in the regulation of IFN -β is not clear. In this project, the inflammasome receptor NLRP3, AIM2 transfer to mitochondria induced by ERS will be detected. Mitochondrial damage like mitochondrial content release to cytoplasm will be determined. The role of activated caspase-1 in the cleavage of DNA sensor cGAG, IFI204 and IFN–β production will be confirmed. Through these studies, the new mechanism of influence of caspase-1 induced by ERS on the final survival of M.bovis will be clarified.

结核病是一种在全球范围内具有重要影响的人畜共患病，是由包括牛分枝杆菌在内的结核分枝杆菌复合群细菌引起。牛分枝杆菌进入巨噬细胞后激活炎症复合体诱导IL-1β的分泌，最新研究报道炎症复合体激活的caspase-1通过直接剪切dsDNA感受器cGAS参与IFN-β的调控；我们前期研究表明牛分枝杆菌感染巨噬细胞引起的内质网应激，可以显著提高IL-1β分泌，但内质网应激如何激活炎症复合体以及激活的Caspase-1是否参与调控IFN-β并不清楚；本项目通过检测内质网应激时炎症复合体受体NLRP3、AIM2向线粒体转移引起线粒体损伤，线粒体内容物进入胞质激活炎症复合体，炎症复合体caspase-1激活对IFN-β分泌的影响，证实牛分枝杆菌感染引起的内质网应激通过激活炎症复合体来调控IL-1β和IFN-β的产生，阐明内质网应激通过调控caspase-1最终影响牛分枝杆菌存活的新机制。

牛分枝杆菌（Mycobacterium bovis, M. bovis）是结核分枝杆菌复合群（mycobacterium tuberculosis complex, MTBC）的成员，是对全球人兽健康、经济社会发展甚至历史进程具有重大影响的人兽共患病致病菌。细胞因子IL-1β和IFN-β分泌可调控免疫应答，对宿主抵抗牛分枝杆菌感染极其重要，但是目前对于宿主调控IL-1β和IFN-β分泌的具体机制尚未完全了解。本实验研究了牛分枝杆菌感染时内质网应激与IL-1β分泌的关系以及炎性复合体活化对IFN-β分泌的影响及其机制，研究证实在体外实验中牛分枝杆菌感染BMDM时诱发的内质网应激可以通过线粒体损伤和炎性复合体活化之间的正反馈循环引起IL-1β大量分泌，另外，炎性复合体的活化还能通过caspase-1降低cGAS，抑制cGAS下游的IFN-β分泌。在体内实验中，内质网应激和炎性复合体活化都有助于降低小鼠肺部牛分枝杆菌负载，减少病理性损伤。实验结果有助于深化人们对牛分枝杆菌感染时内质网应激与炎性体活化以及IL-1β分泌、IFN-β产生路径等相互调控机制的理解，也为深入了解宿主在牛分枝杆菌感染时固有免疫应答的机制以及药物研发和使用提供理论依据