Autophagy in Tuberculosis

结核分枝杆菌每年造成数百万人死亡，其中包括很大比例的 艾滋病毒合并感染者。控制M的宿主防御系统结核病仍有待充分界定。 最近，包括我们在内的几个研究小组已经证明，自噬降解是一个主要的， 以前未被认识到的消除细胞内微生物的机制。我们的工作表明， 自噬是一个可以抑制M.结核病，而且， 在药理学和生理学激动剂的作用下，自噬可以通过免疫学手段控制。 自噬是一种基本的生物学过程，被定义为细胞质稳态途径， 细胞质部分被膜隔离，以递送到溶酶体。这将导致移除 受损或过剩的细胞器和稳定的、长寿的大分子的周转。自噬 先前被牵连在癌症的健康促进和疾病相关状态中， 神经退化、发育和衰老。它最近被证明在感染性疾病中具有保护作用， 疾病代表了以前未被认识到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 分枝巨噬细胞感染期间的结核病。我们的主要假设是， 药理学、生理学和免疫学手段消除细胞内M。结核的 我们的建议的具体目标是：1）描绘自噬途径消除细胞内M。 结核这将使用来自转基因小鼠的巨噬细胞来实现，所述转基因小鼠在以下方面有缺陷： 关键自噬基因，ATG 5和其他最近开发的用于自噬研究的分子工具。 2)定义自噬作为M.结核病防治。重点将放在IFN-γ上 及其下游调节自体免疫的效应子。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，并检查它们在 机械研究。 本项目将描述控制细胞内M.结核病，并显示 自噬可以通过免疫学和药理学手段诱导和调节。我们 研究将提供治疗和预防的新的药理学和免疫学方法 结核病，与免疫和一般传染病的强烈影响。

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.