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.

项目总结