Autophagy in Tuberculosis

结核分枝杆菌每年造成数百万人死亡，包括很大比例的 HIV混合感染的患者。控制结核分枝杆菌的宿主防御机制仍有待充分描述。 最近，包括我们在内的几个组织已经证明，自噬降解是一个主要的， 以前未知的清除细胞内微生物的机制。我们的工作表明， 自噬是一种可以抑制结核分枝杆菌细胞内存活的过程，除了 在药理和生理激动剂的作用下，自噬可以通过免疫学手段来控制。 自噬是一种基本的生物学过程，被定义为细胞质内稳态途径，通过这种途径 细胞质部分被膜隔离，以运送到溶酶体。这会导致删除 损坏或过剩的细胞器以及稳定、长寿的大分子的周转。自噬已经 之前曾被认为与促进健康和癌症相关的状态有关， 神经退化、发育和老化。它最近显示出在传染性疾病中的保护作用 疾病代表了一种以前未被认识的先天和适应性免疫机制。 我们的长期目标是在消除的背景下剖析自噬的分子机制 巨噬细胞感染期间的结核分枝杆菌感染。我们的主要假设是自噬的诱导通过 药物、生理和免疫手段可消除细胞内结核分枝杆菌。这个 我们建议的具体目标是：1)描述消除细胞内M的自噬途径。 肺结核。这将使用来自转基因小鼠的巨噬细胞来完成 关键的自噬基因ATG5和其他最近发展起来的用于自噬研究的分子工具。 2)将自噬定义为控制结核分枝杆菌的免疫效应。重点将放在干扰素-γ上 及其下游的效应器调节自动跳跃。3)确定其他已知的激动剂和 分枝杆菌细胞内存活的拮抗剂影响自噬并检测其作用模式 机械学研究。 该项目将描述控制细胞内结核分枝杆菌的自噬机制，并展示 这种自噬可以通过免疫学和药理学手段来诱导和调节。我们的 研究将为治疗和预防提供新的药理学和免疫学方法 结核病，对免疫和一般传染病有很大影响。

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 autopjiagy. 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.