Sirtuins and Host Metabolism in TB Pathogenesis and Treatment

项目总结 由结核分枝杆菌(Mtb)引起的结核病(TB)是由感染引起的主要死亡原因 由于免疫介导的空化和纤维化，许多结核病幸存者留下了永久性的肺损伤 治愈。Sirtuins(sirtuins，SIRT)是一类能量敏感的NAD+依赖的脱乙酰酶家族，可修饰组蛋白， 转录因子、代谢酶和其他目标，以防御饥饿，恢复动态平衡 应激，支持线粒体的完整性，促进炎症的消退。在出版和未出版中 初步研究发现，SIRT1(主要胞质SIRT)和SIRT3(主要线粒体)的水平 Sirt)在感染结核分枝杆菌(MTB)的巨噬细胞(MΦ)中表达下调。初步 数据支持M-Φ中Mtb抑制SIRT1/3轴改变基因表达水平的模型 三羧酸循环、电子传输链和糖酵解途径。这会导致从氧化的转变 糖酵解的磷酸化，增加线粒体活性氧物种(ROS)的产生，并损害 ROS拾荒者。其结果是增加了线粒体压力和MΦ细胞死亡。糖酵解转变(Warburg 效果)迅速增强MΦ的抗菌性能，但以干扰多个SIRT1/3为代价 导致慢性感染时炎症和结核病严重程度增加的受调控的过程。研究 在目标1中，建立并填补了我们初步数据中的空白，通过体外实验研究了 Mtb下调SIRT1/3及其下游对代谢和表观遗传重编程的影响。目标 2使用现有的SIRT1和SIRT3缺失小鼠品系，以及其他正在开发中的品系，用于气溶胶结核病研究 这将把Aim1的体外数据与体内系统水平的宿主防御联系起来。该项目的最终结果是 用于宿主导向治疗结核病的几种SIRT激动剂的测试。我们预测这些特工将恢复 线粒体动态平衡，加速病变消毒，减轻肺结核免疫病理。其影响 这些药物在体内免疫代谢途径上的作用将在体外数据的背景下进行解释 在目标1中，我们的项目解决了在理解上游触发因素和下游触发因素方面的一个重要差距 沃堡效应在结核病中的后果，同时产生关于潜在疾病的新知识 改善结核病治疗结果和减轻肺结核患者肺损害负担的辅助治疗 幸存者。

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 In published and unpublished preliminary studies, we found that levels of SIRT1 (the major cytosolic SIRT) and SIRT3 (the major mitochondrial SIRT) are downregulated in macrophages (MΦ)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.