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.

项目概要 结核病 (TB) 由结核分枝杆菌 (Mtb) 引起，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 强调对利用宿主内在的宿主导向疗法（HDT）的需求。 使用小分子药物加速灭菌并限制宿主引起的肺损伤的机制 我们报道二甲双胍可降低结核分枝杆菌感染者的肺部细菌负荷和免疫病理学。 超过 50 万接受二甲双胍治疗糖尿病的小鼠的回顾性数据支持了这一观点。 这些研究报告了该药物的 HDT 潜力，降低了 Mtb 感染率和从潜伏感染到进展的发生率。 活动性结核病，减少空洞和全因死亡率，加速痰液转化，减少结核病复发。 该项目的目标是了解二甲双胍 HDT 功效的机制，重点关注炎症 我们的初步数据表明，二甲双胍可扩增非经典 Ly6Clo 单核细胞。 这些细胞以 AMPK 依赖性方式对于先天“训练有素的”免疫中的宿主保护至关重要。 Ly6Clo 单核细胞产生 CXCL10，招募 CD8+CXCR3+ 记忆 (TM) 细胞，参与组织修复。 这可能以抗原特异性和非特异性方式限制结核分枝杆菌的复制。我们的数据还表明。 二甲双胍介导的保护涉及 NOTCH 通路调节，通过抑制 NOTCH1 驱动纤维化并增强 NOTCH2 来调节 Ly6Clo 单核细胞和 CD8+ TM 细胞分化。 目标 1 中的实验将确定保护性保护中对 AMPK 和 NOTCH 信号传导的要求。 使用小鼠气溶胶结核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、胶原重塑引起的肺组织损伤以及转录组和蛋白质组标记 将研究二甲双胍的免疫代谢和表观遗传调节活性。 目标 2 中的实验将确定 CD8+ TM 细胞和 CXCL10- 的要求。 CXCR3 轴在宿主保护中的作用并评估二甲双胍之间的潜在异同 受过教育的 CD8+ TM 细胞和虚拟记忆 T 细胞都包括使用替代方案的验证研究。 小鼠模型（C3HeB/FeJ 和 Collaborative Cross）和去识别的人血浆、血液 RNA 和 来自临床结核病研究的 PBMC 样本，参与者有或没有接触过二甲双胍。 将产生有关二甲双胍 TB-HDT 功效机制的新知识，为设计提供支持 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 与二甲双胍相比，具有更高的特异性、有效性和耐受性。