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: 10620121
• 负责人: Hardy Kornfeld
• 金额: $ 62.86万
• 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/10620121
• 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; Citric Acid Cycle; Data; Deacetylase; Deacetylation; 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; Hypoxia Inducible Factor; Immune; Immunity; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Interleukin-1; Knockout Mice; Knowledge; Left; Lesion; Ligands; Link; Lung; Macrophage; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Methods; 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; improved; in vivo; inhibitor; interest; lung health; lung injury; lung preservation; overexpression; permissiveness; promoter; respiratory; response; sensor; 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.

项目摘要 由结核分枝杆菌（Mycobacterium tuberculosis，Mtb）引起的结核病（tuberculosis，TB）是因感染而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 治愈Sirtuins（SIRTs）是一个能量敏感NAD+依赖性去乙酰化酶家族，其修饰组蛋白， 转录因子，代谢酶和其他目标，以抵御饥饿，恢复稳态， 压力，支持线粒体的完整性，并促进炎症的解决。在出版和未出版的 初步研究，我们发现SIRT 1（主要的胞质SIRT）和SIRT 3（主要的线粒体SIRT）的水平 SIRT）在感染结核分枝杆菌（Mtb）的巨噬细胞（MΦ）中下调。初步 数据支持一个模型，其中MΦ中Mtb对SIRT 1/3轴的抑制改变了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。这导致了氧化性 磷酸化糖酵解，增加线粒体活性氧（ROS）的产生，并损害 ROS清除。结果是线粒体应激和MΦ细胞死亡增加。糖酵解位移（瓦尔堡 效应）迅速增强MΦ抗微生物性能，但以干扰多个SIRT 1/3为代价 调节过程，导致炎症增加和结核病的严重性与慢性感染。研究 在目标1中，我们建立并填补了我们初步数据的空白，通过体外实验研究了 Mtb下调SIRT 1/3以及对代谢和表观遗传重编程的下游影响目的 2使用现有的SIRT 1和SIRT 3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 这将使Aim 1的体外数据与体内系统水平的宿主防御相关。该项目的高潮是 测试用于TB的宿主定向疗法的几种SIRT激动剂。我们预测这些代理人将恢复 线粒体稳态，加速病变灭菌，减少肺结核免疫病理。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器和下游触发器的重要差距。 结核病的瓦尔堡效应的后果，同时产生关于潜在的新知识， 改善结核病治疗结果和减轻结核病肺损害负担的连续性治疗 幸存者