RP4: Harnessing autophagy to treat tuberculosis

RP4：利用自噬治疗结核病

• 批准号: 10573263
• 负责人: MICHAEL SHILOH
• 金额: $ 155.64万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573263
• 关键词: Animal Model; Anti-Infective Agents; Antibiotics; Autophagocytosis; Autophagosome; Bacteria; Cells; Cessation of life; Chemicals; Collaborations; Communicable Diseases; Cytoplasm; 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; Macrophage; Mediating; Medical; Molecular; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Organism; Parkin; Pathologic; Pathway interactions; Peptides; 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; 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 isopeptidase; ubiquitin ligase

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.

项目总结-RP 4 结核分枝杆菌仍然是最具破坏性的人类传染病之一， 每年都有死亡，并潜在地感染了世界三分之一的人口。M.结核病最近演变成 对多种一线抗生素产生耐药性，因此，开发促进杀死 耐药M.肺结核是必要的。其中一种方法是细菌不能进化出耐药性， 是开发一种治疗方法，利用宿主的反应，增强人体自身的系统来杀死M。 结核宿主细胞吞噬并降解细胞内物质的过程称为降解性自噬 细菌最近已成为宿主导向治疗的可能靶点。在上一次CETR中， RP 1 -3，我们鉴定和表征了几种可以利用自噬途径限制M。 结核病在巨噬细胞和体内复制。我们还发现了 自噬启动，细菌成为降解的目标。特别是在M。肺结核感染， 细胞质DNA被蛋白质cGAS和STING检测到，导致自噬起始，而M. 结核杆菌被泛素连接酶Smurf 1靶向降解。另外，我们发现， 自噬蛋白ATG 5可抑制M.结核 感染因此，在拟议的研究中，我们将（1）测试自噬导向化合物对 M.（2）定义和靶向cGAS-STING依赖性的结核病的机制， M.（3）明确结核分枝杆菌感染的机制。 结核病是针对自噬体的Smurf 1和（4）定义和靶向途径参与 在M.肺结核感染。我们预计 这些方法将导致识别先导化合物，用于未来的研究，以建立新的广泛的， 广谱抗感染药