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

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。自噬是一个有助于所有三个方面的保护的过程 结核病（TB）。自噬和相关过程的有效性或失败与 结核病的中心问题。其中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）的组织损伤 系统，以及慢性肺损伤或化疗完成后的急性病症。 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- 结核病相互作用、细胞代谢以及作为细胞/组织保护机制。具体而言，在本次更新中 我们将描述自噬和相关过程如何管理代谢和细胞保护 针对活动性和潜伏性感染中结核分枝杆菌的反应。在结核病背景下定义这些关系时， 我们将揭示对不同健康和病理状态具有重要意义的基本机制 结核病的基本价值和转化价值。 根据我们的最新发现，我们建议重点关注结核分枝杆菌对感染者造成的内膜损伤 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因素。我们 将这组细胞反应称为膜修复、去除和替换（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转换 保护与发病机制，以及活动性结核病与潜伏期。 具体目标是： 目标 1 定义关键自噬因子在预防 Mtb 的体内作用。这一目标将集中于 唯一的整合膜自噬 (ATG) 因子 ATG9 的作用，作为作用的最终测试 自噬膜可预防活动性或潜伏性结核病。我们将使用急性和 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 2. 确定 TBK1 和 ATG9 在自噬关键阶段的作用。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针对 Mtb 的保护。 HIV干扰点将被测试。 目标 3，定义宿主细胞对与 Mtb 感染相关的内膜损伤的反应。我们将 关注内膜损伤，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 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。

项目成果

Targeted pulmonary delivery of inducers of host macrophage autophagy as a potential host-directed chemotherapy of tuberculosis.

• DOI: 10.1016/j.addr.2016.01.016
• 发表时间: 2016-07-01
• 期刊: Advanced drug delivery reviews
• 影响因子: 16.1
• 作者: Gupta A;Misra A;Deretic V
• 通讯作者: Deretic V

Mammalian hybrid pre-autophagosomal structure HyPAS generates autophagosomes.

• DOI: 10.1016/j.cell.2021.10.017
• 发表时间: 2021-11-24
• 期刊: Cell
• 影响因子: 64.5
• 作者: Kumar S;Javed R;Mudd M;Pallikkuth S;Lidke KA;Jain A;Tangavelou K;Gudmundsson SR;Ye C;Rusten TE;Anonsen JH;Lystad AH;Claude-Taupin A;Simonsen A;Salemi M;Phinney B;Li J;Guo LW;Bradfute SB;Timmins GS;Eskelinen EL;Deretic V
• 通讯作者: Deretic V

ATG5 provides host protection acting as a switch in the atg8ylation cascade between autophagy and secretion.

• DOI: 10.1016/j.devcel.2023.03.014
• 发表时间: 2023-04
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Fulong Wang;R. Peters;Jingyue Jia;M. Mudd;M. Salemi;Lee Allers;Ruheena Javed;Thabata Duque;M. Paddar;Einar S. Trosdal;B. Phinney;V. Deretic

TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity.

• DOI: 10.1083/jcb.201503023
• 发表时间: 2015-09-14
• 期刊: The Journal of cell biology
• 作者: Kimura T;Jain A;Choi SW;Mandell MA;Schroder K;Johansen T;Deretic V
• 通讯作者: Deretic V

Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential.

• DOI: 10.1038/ncomms9620
• 发表时间: 2015-10-27
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Chauhan S;Ahmed Z;Bradfute SB;Arko-Mensah J;Mandell MA;Won Choi S;Kimura T;Blanchet F;Waller A;Mudd MH;Jiang S;Sklar L;Timmins GS;Maphis N;Bhaskar K;Piguet V;Deretic V
• 通讯作者: Deretic V