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: 10208211
• 负责人: Hardy Kornfeld
• 金额: $ 66.4万
• 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/10208211
• 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; Health; 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; Lung Inflammation; 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 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/antagonist; interest; 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.

项目摘要 结核分枝杆菌（MTB）引起的结核病（TB）是由于感染引起的死亡的主要原因 由于免疫介导的气蚀和纤维化，许多结核冲浪者都有永久性肺部损害 康复。 Sirtuins（Sirts）是一个能量感应NAD+依赖性脱乙酰基酶的家族，可修饰组蛋白， 转录因子，代谢酶和其他捍卫饥饿的靶标，在恢复体内平衡期间 压力，支持线粒体完整性并促进感染的分辨率。在出版和未出版中 初步研究，我们发现SIRT1（主要的胞质SIRT）和SIRT3（主要线粒体的主要胞质SIRT）水平 SIRT）在感染结核分枝杆菌（MTB）的巨噬细胞（Mφ）中被下调。初步的 数据支持一个模型，其中MTB中MTB抑制Mφ的SIRT1/3轴改变了基因的表达水平 三核酸周期，电子传输链和糖酵解途径。这会导致氧化的转变 磷酸化对糖酵解，增加线粒体活性氧（ROS）的产生，并损害 ROS清除。结果是增加线粒体应激和Mφ细胞死亡。糖酵解转移（Warburg） 效果）迅速增强Mφ抗菌性能，但以扰动多个SIRT1/3的牺牲 调节过程，导致感染和结核病疾病严重程度增加，并随着慢性感染的影响。研究 在AIM 1中建立并填补了我们的初步数据中的空白，并通过体外实验研究了 MTB的SIRT1/3下调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SIRT1和SIRT3 NULL小鼠的菌株以及开发的其他菌株进行气溶胶结核病研究 这将与从AIM1到体内系统水平的防御托管防御的体外数据有关。该项目以 测试几种SIRT激动剂用于宿主定向的结核病治疗。我们预测这些代理商将恢复 线粒体稳态，加速病变灭菌并减少肺结核免疫病理学。效果 这些对体内免疫代谢途径的药物中的体外数据将被解释 在AIM 1中。我们的项目解决了了解上游触发器和下游的重要差距 Warburg效应在结核病中的后果，同时产生有关潜在的新知识 辅助治疗以改善结核病治疗结果并减少结核病中肺部损伤的伯嫩 幸存者。