Lung-Protective Mechanisms of Metformin in TB

二甲双胍治疗结核病的肺保护机制

• 批准号: 10556391
• 负责人: Hardy Kornfeld
• 金额: $ 63.76万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-05 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556391
• 关键词: 5' -AMP-activated protein kinase; Acceleration; Adult; Aerosols; Alveolar; Antigens; Blood; CD44 gene; CD8B1 gene; CXCL10 gene; CXCR3 gene; Cell Differentiation process; Cells; Circulation; Clinical; Clinical Trials; Collagen; Data; Development; Diabetes Mellitus; Disease; Down-Regulation; Drug resistance; Elements; Epigenetic Process; Fibrosis; Frequencies; Gene Expression; Gene Expression Regulation; Goals; Human; ITGAM gene; Immune; Immunity; Impairment; Individual; Infection; Infiltration; Inflammation; Injury; Knowledge; Ligands; Lung; Macrophage; Maintenance; Mediating; Memory; Metformin; Modeling; Morality; Mus; Mycobacterium tuberculosis; Myelogenous; NOTCH1 gene; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Participant; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Phagocytes; Pharmaceutical Preparations; Plasma; Proteomics; Pulmonary Fibrosis; Pulmonary Tuberculosis; RNA; Recurrence; Regimen; Reporting; Resolution; Risk; SELL gene; Sampling; Signal Transduction; Specificity; Spleen; Sputum; Sterilization; Structure of parenchyma of lung; Survivors; T memory cell; T-Lymphocyte; Testing; Therapy trial; Toxic effect; Training; Treatment Efficacy; Tuberculosis; Up-Regulation; adenylate kinase; antifibrotic treatment; antimicrobial; design; experimental study; fibrogenesis; fighting; global health; improved; indium-bleomycin; lung injury; lung preservation; monocyte; mortality; mouse model; new therapeutic target; novel; novel strategies; pulmonary function; recruit; response; small molecule; tissue repair; transcriptome sequencing; transcriptomics; tuberculosis immunity; tuberculosis treatment; validation studies; virtual

PROJECT SUMMARY Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health threat. Challenges of compliance and toxicities of prolonged antimicrobial regimens and increasing drug resistance highlight the need for novel treatment approaches. Host-directed therapy (HDT) harnesses host-intrinsic mechanisms using small molecule drugs to accelerate sterilization and limit lung damage caused by host immunity. We reported that metformin reduced lung bacterial load and immune pathology in Mtb-infected mice. Retrospective data from over half a million individuals treated for diabetes with metformin support the HDT potential of this drug. These studies reported lower rates of Mtb infection and progression from latent to active TB, less cavitation and all-cause mortality, accelerated sputum conversion and less TB recurrence. The goal of this project is to discern the mechanisms of metformin HDT efficacy, focusing on inflammation and fibrosis. Our preliminary data suggest that metformin expands non-classical Ly6Clo monocytes in an AMPK-dependent manner. These cells are essential for host protection in innate “trained” immunity and they participate in tissue repair. Ly6Clo monocytes produce CXCL10 that recruits CD8+CXCR3+ memory (TM) cells, which may restrict Mtb replication in an antigen-specific and non-specific manner. Our data also suggest that metformin-mediated protection involves NOTCH pathway modulation, with suppression of NOTCH1 that drives fibrosis and enhancement of NOTCH2 to regulates Ly6Clo monocyte and CD8+ TM cell differentiation. Experiments in Aim 1 will establish the requirement for AMPK and NOTCH signaling in the protective functions of metformin using the mouse aerosol TB model. Outcomes are lung bacterial load, immune pathology, lung tissue damage with collagen remodeling and transcriptomic and proteomic markers of fibrogenesis. Immunometabolic and epigenetic regulatory activities of metformin will be investigated in the context of TB-HDT. Experiments in Aim 2 will establish the requirements for CD8+ TM cells and the CXCL10- CXCR3 axis in host protection and evaluate potential similarities and differences between metformin- educated CD8+ TM cells and virtual memory T cells. Both Aims include validation studies using alternative mouse models (C3HeB/FeJ and Collaborative Cross) and de-identified human plasma, blood RNA and PBMC samples from clinical TB studies having participants with or without metformin exposure. This project will produce new knowledge about the mechanisms of metformin TB-HDT efficacy that will support the design and interpretation of human clinical trials using metformin and might identify new targets for HDT agents having greater specificity, efficacy and tolerability than metformin.

项目摘要 由结核分枝杆菌（Mycobacterium tuberculosis，Mtb）引起的结核病（TB）仍然是全球主要的健康威胁。 长期抗菌治疗方案的依从性和毒性以及耐药性增加的挑战 强调需要新的治疗方法。宿主导向治疗（HDT）利用宿主内在 使用小分子药物加速灭菌和限制宿主引起的肺损伤的机制 免疫力我们报道了二甲双胍降低结核分枝杆菌感染者的肺细菌负荷和免疫病理学， 小鼠来自50多万接受二甲双胍治疗的糖尿病患者的回顾性数据支持 这种药物的HDT潜力。这些研究报告了较低的结核分枝杆菌感染率和从潜伏期到潜伏期的进展。 活动性结核病，减少空洞和全因死亡率，加速痰菌转化和减少结核病复发。 本项目的目标是识别二甲双胍HDT疗效的机制，重点是炎症 和纤维化。我们的初步数据表明，二甲双胍可扩增非经典Ly 6Clo单核细胞。 AMPK依赖性方式。这些细胞在先天“训练”免疫中对宿主保护是必不可少的， 参与组织修复。Ly 6Clo单核细胞产生CXCL 10，其募集CD 8 + CXCR 3+记忆（TM）细胞， 其可以以抗原特异性和非特异性方式限制Mtb复制。我们的数据还表明， 二甲双胍介导的保护作用涉及NOTCH途径的调节，抑制NOTCH 1， 驱动纤维化和增强NOTCH 2以调节Ly 6Clo单核细胞和CD 8 + TM细胞分化。 目标1中的实验将建立保护性细胞中AMPK和NOTCH信号传导的要求。 使用小鼠气溶胶TB模型研究二甲双胍的功能。结果是肺部细菌负荷、免疫 病理学，肺组织损伤与胶原重塑和转录组学和蛋白质组学标志物， 纤维化二甲双胍的免疫代谢和表观遗传调节活性将在 TB-HDT的背景。目标2中的实验将确定对CD 8 + TM细胞和CXCL 10-的要求 CXCR 3轴在宿主保护中的作用，并评价二甲双胍- 受教育的CD 8 + TM细胞和虚拟记忆T细胞。两个目的均包括使用替代方法的验证研究 小鼠模型（C3 HeB/FeJ和Collaborative Cross）和去识别的人血浆、血液RNA和 来自临床TB研究的PBMC样本，受试者有或没有二甲双胍暴露。这个项目 将产生关于二甲双胍TB-HDT疗效机制的新知识，以支持设计 和解释使用二甲双胍的人体临床试验，并可能确定HDT药物的新靶点 具有比二甲双胍更高的特异性、功效和耐受性。