Sirtuins and Host Metabolism in TB Pathogenesis and Treatment

Sirtuins 和宿主代谢在结核病发病机制和治疗中的作用

• 批准号: 10390487
• 负责人: Hardy Kornfeld
• 金额: $ 63.64万
• 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: 2021-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390487
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acetylation; Address; Aerosols; Agonist; Animal Model; Antibiotic Therapy; Cause of Death; Cell Death; Cell Line; Cells; Chronic; Citric Acid Cycle; Data; Deacetylase; Development; Dose; Down-Regulation; Electron Transport; Engineering; Environment; Enzymes; Epigenetic Process; Equilibrium; Event; Family; Fibrosis; Genes; Genus Mycobacterium; Germ; Glycolysis; Hexokinase 2; Histone Acetylation; Histones; Homeostasis; Host Defense; Immune; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Interleukin-1; Knockout Mice; Knowledge; Lead; Left; Lesion; Ligands; Link; Lung; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Mitochondria; Modeling; Mus; Mycobacterium tuberculosis; Myelogenous; Necrosis; Nicotinamide adenine dinucleotide; Outcome; Oxidative Phosphorylation; Oxidative Stress; PPAR gamma; Pathogenesis; Pathology; Pathway interactions; Performance; Predisposition; Process; Production; Publishing; Pulmonary Inflammation; Pulmonary Pathology; Pulmonary Tuberculosis; Reactive Oxygen Species; Receptor Signaling; Repression; Resolution; Role; SIRT1 gene; Severities; Severity of illness; Sirtuins; Starvation; Sterilization; Stress; Survivors; Testing; Time; Toll-like receptors; Treatment outcome; Tricarboxylic Acids; Tuberculosis; Warburg Effect; aerobic glycolysis; antimicrobial; chronic infection; cytokine; experimental study; falls; healing; hypoxia inducible factor 1; improved; in vivo; inhibitor; interest; lung health; lung injury; lung preservation; macrophage; overexpression; promoter; respiratory; response; sex; single-cell RNA sequencing; transcription factor; transcriptomics; tuberculosis treatment

PROJECT SUMMARY Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death due to infection and many TB survivors are left with permanent lung impairment due to immune-mediated cavitation and fibrotic healing. Sirtuins (SIRTs) are a family of energy-sensing NAD+-dependent deacetylases that modify histones, transcription factors, metabolic enzymes, and other targets to defend starvation, restore homeostasis during stress, support mitochondrial integrity, and promote the resolution of inflammation. In published and unpublished preliminary studies, we found that levels of SIRT1 (the major cytosolic SIRT) and SIRT3 (the major mitochondrial SIRT) are downregulated in macrophages (MΦ) infected with Mycobacterium tuberculosis (Mtb). Preliminary data support a model in which SIRT1/3 axis suppression by Mtb in MΦ alters the expression levels of genes in the tricarboxylic acid cycle, electron transport chain, and glycolytic pathway. This causes a shift from oxidative phosphorylation to glycolysis, increases production of mitochondrial reactive oxygen species (ROS), and impairs ROS scavenging. The result is increased mitochondrial stress and MΦ cell death. The glycolytic shift (Warburg effect) rapidly enhances MΦ antimicrobial performance but at the expense of perturbing multiple SIRT1/3 regulated processes that lead to increased inflammation and TB disease severity with chronic infection. Studies in Aim 1 build on and fill gaps in our preliminary data, with in vitro experiments investigating the mechanism of SIRT1/3 downregulation by Mtb and the downstream effects on metabolic and epigenetic reprogramming. Aim 2 uses existing strains of SIRT1 and SIRT3 null mice, and other strains in development, for aerosol TB studies that will relate in vitro data from Aim1 to host defense at the systemic level in vivo. The project culminates with testing of several SIRT agonists for host-directed therapy of TB. We predict that these agents will restore mitochondrial homeostasis, hasten lesion sterilization, and reduce pulmonary TB immune pathology. The effects of these agents on immunometabolic pathways in vivo will be interpreted in the context of in vitro data produced in Aim 1. Our project addresses an important gap in understanding the upstream triggers and downstream consequences of the Warburg effect in TB while at the same time producing new knowledge about potential adjunctive treatments to improve TB treatment outcomes and reduce the burden of pulmonary impairment in TB survivors.

项目概要 结核病 (TB) 由结核分枝杆菌 (Mtb) 引起，是感染导致死亡的主要原因 许多结核病幸存者由于免疫介导的空洞和纤维化而留下永久性肺损伤 Sirtuins (SIRT) 是一类能量感应 NAD+ 依赖性脱乙酰酶，可修饰组蛋白、 转录因子、代谢酶和其他目标来防御饥饿，恢复体内平衡 压力，支持线粒体完整性，并促进炎症的解决。 初步研究，我们发现 SIRT1（主要的细胞质 SIRT）和 SIRT3（主要的线粒体 SIRT）水平 SIRT）在感染结核分枝杆菌（Mtb）的巨噬细胞（MΦ）中下调。 数据支持这样一个模型：MΦ 中 Mtb 抑制 SIRT1/3 轴改变了 MΦ 中基因的表达水平。 三羧酸循环、电子传递链和糖酵解途径这导致氧化途径的转变。 磷酸化为糖酵解，增加线粒体活性氧 (ROS) 的产生，并损害 ROS 清除导致线粒体应激增加和 MΦ 细胞死亡（Warburg）。 效应）迅速增强 MΦ 抗菌性能，但代价是扰乱多个 SIRT1/3 导致炎症增加和慢性感染结核病严重程度的调节过程。 目标 1 建立在我们初步数据的基础上并填补空白，通过体外实验研究了 Mtb 下调 SIRT1/3 及其对代谢和表观遗传重编程的下游影响。 2 使用现有的 SIRT1 和 SIRT3 缺失小鼠品系以及正在开发的其他品系进行气溶胶结核病研究 该项目将把 Aim1 的体外数据与体内系统水平的宿主防御联系起来。 测试了几种 SIRT 激动剂用于宿主定向治疗的结核病，我们预测这些药物将会恢复。 线粒体稳态，加速病灶灭菌，减轻肺结核免疫病理的影响。 这些药物对体内免疫代谢途径的影响将在产生的体外数据的背景下进行解释 目标 1。我们的项目解决了理解上游触发因素和下游触发因素方面的一个重要差距 瓦尔堡效应对结核病的影响，同时产生了关于潜力的新知识 辅助治疗可改善结核病治疗结果并减轻结核病肺损伤的负担 幸存者。