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: 10338184
• 负责人: Hardy Kornfeld
• 金额: $ 64.79万
• 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/10338184
• 关键词: Adult; Aerosols; Alveolar; Antigens; Blood; Blood Circulation; CD44 gene; CD8B1 gene; CXCL10 gene; CXCR3 gene; Cell Differentiation process; Cell Maintenance; Cells; Clinical; Clinical Trials; Collagen; Data; Development; Diabetes Mellitus; Disease; Down-Regulation; Drug resistance; Elements; Epigenetic Process; Fibrosis; Frequencies; Gene Expression; Genes; Goals; Human; ITGAM gene; Immune; Immunity; Impairment; Individual; Infection; Inflammation; Injury; Knowledge; Ligands; Lung; 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; macrophage; 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 结核分枝杆菌（MTB）引起的结核病（TB）仍然是全球的主要健康威胁。 长期抗菌治疗方案的合规性和毒性的挑战和耐药性的增加 强调需要采用新型治疗方法。宿主定向疗法（HDT）线束宿主intrinsic 使用小分子药物加速灭菌并限制宿主造成的肺损伤的机制 免疫。我们报道了二甲双胍减少了MTB感染的肺细菌负荷和免疫病理 老鼠。来自二甲双胍接受治疗的超过一百万个患者的回顾性数据支持 该药物的高清电势。这些研究报告了MTB感染率较低，从潜在到 主动结核，较少的气蚀和全因死亡率，加速痰液转化和较少的结核病复发。 该项目的目的是辨别二甲双胍HDT效率的机制，重点关注炎症 和纤维化。我们的初步数据表明，二甲双胍在一个 依赖AMPK的方式。这些细胞对于先天“训练”免疫的宿主保护至关重要，它们是 参与组织修复。 LY6CLO单核细胞产生的CXCL10募集CD8+ CXCR3+内存（TM）细胞， 这可能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涉及Notch途径调节，并抑制了Notch1 驱动Notch2的纤维化和增强，以调节LY6CLO单核细胞和CD8+ TM细胞分化。 AIM 1中的实验将确定受​​保护的AMPK和Notch信号的要求 使用小鼠气溶胶结核病模型的二甲双胍功能。结果是肺细菌负荷，免疫 病理学，肺组织损伤，胶原蛋白重塑以及转录组和蛋白质组学标记 纤维发生。将研究二甲双胍的免疫代谢和表观遗传调节活性 TB-HDT的上下文。 AIM 2中的实验将确定CD8+ TM细胞和CXCL10-的要求 宿主保护中的CXCR3轴并评估二甲双胍之间的潜在相似性和差异 受过教育的CD8+ TM细胞和虚拟记忆T细胞。两个目的包括使用替代方案的验证研究 小鼠模型（C3HEB/FEJ和协作十字架）和识别的人血浆，血液RNA和 来自临床结核病研究的PBMC样品，有或没有二甲双胍的参与者。这个项目 将为二甲双胍TB-HDT效率的机制提供新的知识，以支持设计 并使用二甲双胍对人类临床试验进行解释，并可能确定HDT剂的新目标 比二甲双胍具有更大的特异性，效率和耐受性。