Autophagy Against Tuberculosis and HIV

结核分枝杆菌(Mtb)感染的结局取决于宿主的免疫、代谢和组织- 保护性反应。自噬是一个过程，它有助于所有三个方面的保护 结核病(TB)。自噬和相关过程的有效性或失败与 结核病的核心问题。这些包括结核病和艾滋病毒之间的勾结，免疫代谢和 糖尿病的代谢失调，肺或其他器官如中枢神经的组织损害 化疗结束后出现慢性肺损伤或急性情况。 该项目旨在定义自噬和相关过程在活动性结核病、结核病潜伏期、艾滋病毒- 结核的相互作用、细胞新陈代谢以及作为细胞/组织保护机制。具体地说，在这次更新中 应用我们将描述自噬和相关过程如何引导代谢和细胞保护 活动性感染和潜伏性感染对结核分枝杆菌的反应。当在结核病的环境中定义这些关系时， 我们将揭示两者不同健康和病理状态的重要基本机制 结核病的基本价值和转换价值。 根据我们的最新发现，我们建议将重点放在结核杆菌对感染的子宫内膜的损害上。 巨噬细胞，作为宿主免疫病理和免疫代谢级联变化的触发器。我们 将这一组细胞反应称为膜修复、移除和替换(MERET)。自噬是 MERET的一个关键方面，但MERET还包括与组织相关的免疫代谢开关 预防与发病机制，以及活动性结核病与潜伏期。 具体目标是： 目的1确定关键自噬因子在体内对结核分枝杆菌的保护作用。这一目标将集中在 唯一的完整膜自噬(ATG)因子的作用，ATG9，作为最终测试的作用 抗活动性或潜伏性结核病的自噬膜。我们将使用急性和非酒精性胃炎的小鼠模型 慢性结核分枝杆菌感染，以测试自噬是阻止还是有利于向潜伏感染过渡。 目的2.确定TBK1和ATG9在自噬关键阶段中的作用。我们将重点关注 ATG9和TBK1以及这些因素如何促进细胞质动态平衡和对结核分枝杆菌的保护。 将对艾滋病毒干扰点进行测试。 目的3，明确宿主细胞对结核分枝杆菌感染相关的膜损伤的反应。我们会 关注内膜损伤，这是一种耐人寻味但知之甚少的现象，发生在结核分枝杆菌感染期间 巨噬细胞感染。我们将检验这样一个假设，即结核分枝杆菌引起的宿主细胞膜损伤是一种 结核病自噬和免疫代谢控制的关键决定因素。

The outcome of Mycobacterium tuberculosis (Mtb) infection depends on host’s immune, metabolic and tissue- protective responses. Autophagy is a process that contributes to all three aspects of protection against tuberculosis (TB). The effectiveness or failure of autophagy and related processes is of direct relevance for central issues in TB. These include collusion between tuberculosis and HIV, immunometabolism and metabolic dysregulation in diabetes, tissue damage in the lung or other organs such as the central nervous system, and chronic pulmonary impairment or acute conditions following completion of chemotherapy. This project intends to define the role of autophagy and associated processes in active TB, TB latency, HIV- TB interactions, cellular metabolism, and as a cell/tissue-protective mechanism. Specifically, in this renewal application we will delineate how autophagy and related processes marshal metabolic and cytoprotective responses against Mtb in active and latent infection. While defining these relationships in the context of TB, we will uncover fundamental mechanisms of significance for diverse health and pathological states of both basic and translational value in TB. Based on our latest findings, we propose to focus on the endomembrane damage inflicted by Mtb in infected macrophages, as a trigger of cascading immunopathological and immunometabolic changes in the host. We refer to this set of cellular responses as membrane repair, removal and replacement (MERET). Autophagy is a key aspect of MERET, but MERET also includes immunometabolic switching, of relevance for tissue protection vs. pathogenesis, and for active TB disease vs. latency. The specific aims are: Aim 1 Define the in vivo role of key autophagy factors in protection against Mtb. This aim will focus on the role of the sole integral membrane autophagy (ATG) factor, ATG9, as the ultimate test of the role of autophagic membranes in protection against active or latent TB. We will use murine models of acute and chronic Mtb infection to test whether autophagy prevents or favors transitions to latent infection. Aim 2. Determine the roles of TBK1 and ATG9 during critical stages of autophagy. We will focus on ATG9 and TBK1 and how these factors contribute to cytoplasmic homeostasis and protection against Mtb. Points of HIV interference will be tested. Aim 3, Define host cell responses to endomembrane damage associated with Mtb infection. We will focus on endomembrane damage, an intriguing but poorly understood phenomenon occurring during Mtb infection of macrophages. We will test the hypothesis that host cell membrane damage caused by Mtb is a critical determinant of autophagic and immunometabolic control of TB.