Autophagy Against Tuberculosis and HIV

自噬对抗结核病和艾滋病毒

• 批准号: 9769998
• 负责人: VOJO P DERETIC
• 金额: $ 74.45万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769998
• 关键词: AIDS/HIV problem; Acute; Address; Anti-Bacterial Agents; Autophagocytosis; Cell membrane; Cells; Chronic; Clinical; Diabetes Mellitus; Dimensions; Disease; Disease Outbreaks; Drug resistance; Drug resistance in tuberculosis; Effectiveness; Epidemic; Equilibrium; Excision; Failure; Funding; Goals; HIV; HIV/TB; Health; Homeostasis; Immune; Impairment; Infection; Infectious Diseases Research; Inflammation; Intervention; Knowledge; Linezolid; Link; Lung; Malnutrition; Marshal; Membrane; Messenger RNA; Metabolic; Metabolic Control; Metabolism; Multi-Drug Resistance; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Natural Immunity; Nerve Degeneration; Neuraxis; Obesity; Organ; Outcome; Pathogenesis; Pathologic; Patients; Pattern; Positron-Emission Tomography; Process; Public Health; Quality Control; Regimen; Research; Risk; Risk Factors; Role; System; TBK1 gene; Testing; Tissues; Tuberculosis; X-Ray Computed Tomography; adaptive immunity; bactericide; base; chemotherapy; in vivo; interest; latent infection; macrophage; mouse model; 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（Mycobacterium tuberculosis，Mtb）感染的转归取决于宿主的免疫、代谢和组织- 保护性反应。自噬是一个过程，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以下因素直接相关： 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， 糖尿病中的代谢失调、肺或其他器官如中枢神经系统的组织损伤 系统和慢性肺损伤或完成化疗后的急性病症。 该项目旨在确定自噬和相关过程在活动性结核病，结核病潜伏期，艾滋病毒- TB相互作用、细胞代谢以及作为细胞/组织保护机制。具体来说，在这次更新中， 应用中，我们将描述自噬和相关过程如何元帅代谢和细胞保护 在活动性和潜伏性感染中对Mtb的应答。在结核病背景下定义这些关系时， 我们将揭示不同的健康和病理状态的重要性的基本机制， 结核病的基本和转化价值。 基于我们的最新研究结果，我们建议关注结核分枝杆菌对感染者内膜的损伤， 巨噬细胞，作为宿主中级联免疫病理学和免疫代谢变化的触发器。我们 将这组细胞反应称为膜修复、去除和替换（MERET）。自噬是 这是MERT的一个关键方面，但MERT还包括与组织相关的免疫代谢转换， 保护与发病机制，以及活动性TB疾病与潜伏期。 具体目标是： 目的1确定关键自噬因子在抗结核杆菌保护中的体内作用。这一目标将侧重于 唯一完整的膜自噬（ATG）因子，ATG 9的作用，作为最终测试的作用， 自噬膜在预防活动性或潜伏性TB中的作用。我们将使用急性和慢性炎症的小鼠模型， 慢性Mtb感染，以测试自噬是否阻止或促进向潜伏感染的转变。 目标二。确定TBK 1和ATG 9在自噬关键阶段的作用。我们将专注于 ATG 9和TBK 1以及这些因子如何有助于细胞质稳态和抗Mtb的保护。 将检测HIV干扰点。 目的3.明确结核分枝杆菌感染引起的细胞内膜损伤的反应。我们将 重点关注内膜损伤，这是一种有趣但知之甚少的现象，发生在结核病期间， 巨噬细胞感染。我们将检验由结核分枝杆菌引起的宿主细胞膜损伤是一种 自噬和免疫代谢控制结核病的关键决定因素。