Autophagy in Tuberculosis

描述（由申请人提供）：结核分枝杆菌每年造成数百万人死亡，其中包括很大一部分合并感染艾滋病毒的患者。控制结核分枝杆菌的宿主防御机制还有待进一步研究。最近，包括我们在内的几个研究小组已经证明，自噬降解是一种主要的、以前未被认识到的细胞内微生物消除机制。我们的工作表明，自噬是一个可以抑制结核分枝杆菌细胞内存活的过程，除了药物和生理激动剂；自噬可以通过免疫手段加以控制。

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is responsible for millions of deaths annually, including a large proportion of HIV co-infected patients. The host defenses controlling M. tuberculosis remain to be fully delineated. Recently, several groups, including ours, have demonstrated that autophagic degradation is a major, previously unrecognized mechanism for elimination of intracellular microbes. Our work has shown that autophagy is a process that can inhibit intracellular survival of M. tuberculosis and that in addition to pharmacological and physiological agonists; autophagy can be controlled by immunological means. Autophagy is a fundamental biological process defined as a cytoplasmic homeostasis pathway whereby cytoplasm portions become sequestered by membrane for delivery to lysosomes. This leads to removal of damaged or surplus organelles and turnover of stable, long-lived macromolecules. Autophagy has been previously implicated in both health-promoting and disease-associated states in cancer, neurodegeneration, development, and aging. Its recently demonstrated protective role in infectious diseases represents a previously unrecognized innate and adaptive immunity mechanism. Our long-term goals are to dissect the molecular mechanisms of autophagy in the context of elimination of M. tuberculosis during macrophage infection. Our main hypothesis is that induction of autophagy by pharmacological, physiological, and immunological means eliminates intracellular M. tuberculosis. The specific aims of our proposal are: 1) Delineate autophagy pathways eliminating intracellular M. tuberculosis. This will be accomplished using macrophages derived from transgenic mice defective in a key autophagy gene, ATG5, and other recently developed molecular tools for autophagy investigations. 2) Define autophagy as an immunological effector of M. tuberculosis control. The focus will be on IFN-y and its downstream effectors modulating autophagy. 3) Determine how other known agonists and antagonists of mycobacterial intracellular survival affect autophagy and examine their mode of action in mechanistic studies. This project will delineate autophagic mechanisms that control intracellular M. tuberculosis, and show that autophagy can be induced and modulated by immunological and pharmacological means. Our studies will provide novel pharmacological and immunological approaches in treatment and prophylaxis of tuberculosis, with strong implications for immunity and infectious diseases in general.