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RP4: Harnessing autophagy to treat tuberculosis

RP4：利用自噬治疗结核病

基本信息

批准号：
10364726
负责人：
MICHAEL SHILOH
金额：
$ 143.51万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10364726
关键词：
Animal Model Anti-Infective Agents Antibiotics Autophagocytosis Autophagosome Bacteria Cells Cessation of life Chemicals Collaborations Communicable Diseases DNA Dependence Development Drug resistance Drug resistance in tuberculosis Drug resistant Mycobacteria Tuberculosis Endoplasmic Reticulum Evolution Future Goals Growth Host Defense Mechanism Human Immune Immune response Inflammation Interferon Type II Knock-in Mouse Lead Life Link Lung Lysosomes Mediating Medical Molecular Multidrug-Resistant Tuberculosis Mycobacterium tuberculosis National Institute of Allergy and Infectious Disease Organism Parkin Pathologic Pathway interactions Physiological Population Pre-Clinical Model Process Proteins Proteomics Regulation Research Research Project Grants Research Project Summaries Resistance Role Signal Transduction Site Stimulator of Interferon Genes Sting Injury System Testing Therapeutic Tuberculosis United States National Institutes of Health Validation bropirimine cytokine drug-sensitive efficacy testing global health immunopathology immunoregulation in vivo innovation macrophage neutrophil new combination therapies novel novel strategies novel therapeutics pathogen phosphoric diester hydrolase prevent priority pathogen programs protective effect public health priorities response sensor synergism therapeutic development therapeutic target tuberculosis treatment ubiquitin ligase

项目摘要

PROJECT SUMMARY – RP4 Mycobacterium tuberculosis remains one of the most devastating human infectious diseases, causing two million deaths annually and latently infecting a third of the world’s population. M. tuberculosis has recently evolved to become resistant to multiple first-line antibiotics, and as such, developing approaches to facilitate the killing of drug-resistant M. tuberculosis are needed. One such approach for which the bacteria cannot evolve resistance is to develop therapeutics that harness the host response, enhancing the body’s own systems for killing M. tuberculosis. The host process called degradative autophagy by which cells engulf and degrade intracellular bacteria has recently emerged as a possible target for host-directed therapy. In the prior CETR, together with RP1-3, we identified and characterized several molecules that can harness the autophagy pathway to restrict M. tuberculosis replication in macrophages and in vivo. We also discovered molecular mechanisms by which autophagy is initiated and bacteria targeted for degradation. Specifically, during M. tuberculosis infection, cytoplasmic DNA is detected by the proteins cGAS and STING, leading to autophagy initiation, while M. tuberculosis is targeted for degradation by the ubiquitin ligase Smurf1. In addition, we discovered that a core autophagy protein, ATG5, suppressed pathologic neutrophilic inflammation in the context of M. tuberculosis infection. Thus, in the proposed research we will (1) Test autophagy-directed compounds for activity against M. tuberculosis in preclinical models, (2) Define and target mechanisms of cGAS-STING-dependent autophagy activation during M. tuberculosis infection, (3) Define and target mechanisms by which M. tuberculosis is targeting to autophagosomes by Smurf1 and (4) Define and target pathways involved in ATG5-mediated control of neutrophilic inflammation during M. tuberculosis infection. We anticipate that these approaches will result in identification of lead compounds for future studies to establish new broad- spectrum anti-infectives.

项目摘要 – RP4 结核分枝杆菌仍然是最具破坏性的人类传染病之一，造成 200 万人死亡每年都有人死亡，并潜伏感染世界三分之一的人口。结核分枝杆菌最近进化为对多种一线抗生素产生耐药性，因此，开发有助于杀死它们的方法需要耐药结核分枝杆菌。细菌无法进化出抗药性的一种这样的方法的目标是开发利用宿主反应的疗法，增强人体自身的杀死支原体的系统。结核。宿主过程称为降解自噬，细胞通过该过程吞噬并降解细胞内的细菌最近已成为宿主定向治疗的可能靶标。在之前的 CETR 中，连同 RP1-3，我们鉴定并表征了几种可以利用自噬途径限制结核分枝杆菌的分子。结核病在巨噬细胞和体内的复制。我们还发现了分子机制自噬被启动，细菌被靶向降解。具体而言，在结核分枝杆菌感染期间，细胞质 DNA 由蛋白质 cGAS 和 STING 检测，导致自噬启动，而 M. 结核菌是泛素连接酶 Smurf1 降解的目标。此外，我们还发现了一个核心自噬蛋白 ATG5 可抑制结核分枝杆菌中的病理性中性粒细胞炎症感染。因此，在拟议的研究中，我们将 (1) 测试自噬导向化合物的活性临床前模型中的结核分枝杆菌，(2) cGAS-STING 依赖的定义和目标机制结核分枝杆菌感染期间的自噬激活，(3) 定义和靶向结核分枝杆菌感染的机制。结核病通过 Smurf1 靶向自噬体，并且 (4) 定义和靶向参与的途径 ATG5 介导的结核分枝杆菌感染期间中性粒细胞炎症的控制。我们预计这些方法将导致先导化合物的鉴定，用于未来的研究，以建立新的广泛的谱抗感染药。