Autophagy in Tuberculosis

描述(申请人提供)：结核分枝杆菌每年造成数百万人死亡，包括很大比例的艾滋病毒合并感染患者。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小组已经证明，自噬降解是消除细胞内微生物的一种以前未被认识到的主要机制。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外，自噬可以通过免疫学手段进行控制。 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，细胞质部分被膜隔离并输送到溶酶体。这会导致损坏或多余的细胞器的移除，以及稳定的、长寿的大分子的周转。自噬以前被认为与促进健康和疾病相关的癌症、神经退行性变、发育和衰老状态有关。它最近在传染病中的保护作用代表了一种以前未被认识的先天性和获得性免疫机制。 我们的长期目标是在巨噬细胞感染过程中消除结核分枝杆菌的背景下，剖析自噬的分子机制。我们的主要假设是，通过药理学、生理学和免疫学方法诱导自噬可以消除细胞内的结核分枝杆菌。我们建议的具体目标是：1)描述消除细胞内结核分枝杆菌的自噬途径。这将使用来自自噬关键基因ATG5缺陷的转基因小鼠的巨噬细胞和其他最近开发的用于自噬研究的分子工具来完成。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及其下游调控自噬的效应器上。3)确定其他已知的分枝杆菌细胞内存活的激动剂和拮抗剂如何影响自噬，并在机制研究中检查它们的作用模式。 该项目将描述控制细胞内结核分枝杆菌的自噬机制，并表明自噬可以通过免疫学和药理学手段来诱导和调节。我们的研究将为结核病的治疗和预防提供新的药理学和免疫学方法，对免疫和一般传染病具有重要意义。

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.