Autophagy Against Tuberculosis and HIV

自噬对抗结核病和艾滋病毒

• 批准号: 10570827
• 负责人: VOJO P DERETIC
• 金额: $ 73.7万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570827
• 关键词: Acute; Address; Anti-Bacterial Agents; Autophagocytosis; Cell membrane; Cells; Central Nervous System; Chronic; Clinical; Cytoplasm; Cytoprotection; Diabetes Mellitus; Dimensions; Disease; Disease Outbreaks; Drug resistance; Drug resistant Mycobacteria Tuberculosis; Effectiveness; Epidemic; Equilibrium; Excision; Failure; Funding; Goals; HIV; HIV/AIDS; HIV/TB; Health; Homeostasis; Immune; Impairment; Infection; Infectious Diseases Research; Inflammation; Intervention; Knowledge; Linezolid; Link; Lung; Macrophage; Malnutrition; Membrane; Meningeal Tuberculosis; Messenger RNA; Metabolic; Metabolic Control; Metabolism; Multi-Drug Resistance; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Natural Immunity; Nerve Degeneration; Obesity; Organ; Outcome; Pathogenesis; Pathologic; Patients; Pattern; Positron-Emission Tomography; Predisposition; Process; Public Health; Quality Control; Recurrence; Regimen; Research; Risk; Risk Factors; Role; System; TBK1 gene; Testing; Tissues; Tuberculosis; X-Ray Computed Tomography; adaptive immunity; bactericide; chemotherapy; co-infection; in vivo; interest; latent infection; mouse model; neuropathology; novel therapeutics; nutritional approach; prevent; programs; repaired; response; standard care; Acute; Address; Anti-Bacterial Agents; Autophagocytosis; Cell membrane; Cells; Central Nervous System; Chronic; Clinical; Cytoplasm; Cytoprotection; Diabetes Mellitus; Dimensions; Disease; Disease Outbreaks; Drug resistance; Drug resistant Mycobacteria Tuberculosis; Effectiveness; Epidemic; Equilibrium; Excision; Failure; Funding; Goals; HIV; HIV/AIDS; HIV/TB; Health; Homeostasis; Immune; Impairment; Infection; Infectious Diseases Research; Inflammation; Intervention; Knowledge; Linezolid; Link; Lung; Macrophage; Malnutrition; Membrane; Meningeal Tuberculosis; Messenger RNA; Metabolic; Metabolic Control; Metabolism; Multi-Drug Resistance; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Natural Immunity; Nerve Degeneration; Obesity; Organ; Outcome; Pathogenesis; Pathologic; Patients; Pattern; Positron-Emission Tomography; Predisposition; Process; Public Health; Quality Control; Recurrence; Regimen; Research; Risk; Risk Factors; Role; System; TBK1 gene; Testing; Tissues; Tuberculosis; X-Ray Computed Tomography; adaptive immunity; bactericide; chemotherapy; co-infection; in vivo; interest; latent infection; mouse model; neuropathology; novel therapeutics; nutritional approach; prevent; programs; repaired; response; standard care

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.

结核分枝杆菌（MTB）感染的结果取决于宿主的免疫，代谢和组织 保护性反应。自噬是一个有助于保护所有三个方面的过程 结核病（TB）。自噬和相关过程的有效性或失败是直接相关的 结核病的中心问题。这些包括结核病和HIV之间的勾结，免疫代谢和 糖尿病的代谢失调，肺部或其他器官（例如中枢神经）的组织损伤 化学疗法完成后，系统以及慢性肺部损伤或急性疾病。 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，HIV-的作用 结核病相互作用，细胞代谢和细胞/组织保护机制。具体而言，在此续约中 应用我们将描述自噬和相关过程元帅代谢和细胞保护 在活性和潜在感染中针对MTB的反应。在结核背景下定义这些关系时， 我们将发现对潜水员健康和病理状态的重要性的基本机制 结核病中的基本和翻译价值。 根据我们的最新发现，我们建议将重点放在MTB造成的恩子膜损害上 巨噬细胞是宿主中级联免疫病理和免疫代谢变化的触发因素。我们 请参阅这组细胞反应作为膜修复，去除和置换（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转换 保护与发病机理，以及用于活跃的结核病疾病与潜伏期。 具体目的是： AIM 1定义了关键自噬因素在保护MTB中的体内作用。这个目标将重点放在 唯一积分膜自噬（ATG）因子ATG9的作用，作为对的作用的最终检验 自噬膜可防止活性或潜在结核。我们将使用急性的鼠模型 慢性MTB感染以测试自噬是防止或有利于过渡到潜在感染。 AIM 2。在自噬的关键阶段确定TBK1和ATG9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稳态和对MTB的保护。 将测试HIV干扰点。 AIM 3，定义了与MTB感染相关的内膜损伤的宿主细胞反应。我们将 专注于内膜损伤，这是MTB期间发生的一种有趣但知之甚少的现象 巨噬细胞的感染。我们将检验以下假设：MTB造成的宿主细胞膜损伤是一个 TB的自噬和免疫代谢控制的关键确定剂。