One-carbon metabolism and immune cell function in tuberculosis

结核病中的一碳代谢和免疫细胞功能

• 批准号: 10719273
• 负责人: Padmini Salgame
• 金额: $ 78.42万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-02 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719273
• 关键词: Adult; Advanced Development; Animal Model; Antimycobacterial Agents; Antitubercular Agents; Area; Biology; C3HeB/FeJ Mouse; Carbon; Cell Lineage; Cell physiology; Cells; Chronic; Communicable Diseases; Complement; Cysteine; Development; Dietary intake; Disease; Disease Progression; Enzymes; Feedback; Folic Acid; Folic Acid Deficiency; Formates; Gene Expression Profiling; Generations; Glutathione; Glycine; Homeostasis; Immune; Immunity; Infection; Infection Control; Inflammatory; Knockout Mice; Lung; Macrophage; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methionine; Methods; Methylation; Mitochondria; Mouse Strains; Mus; Mycobacterium tuberculosis; Myeloid Cells; NADH; NADP; Natural Immunity; Oxidation-Reduction; Oxidoreductase; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Population; Predisposition; Proliferating; Property; Pulmonary Pathology; Purine Nucleotides; Reaction; Research; Research Personnel; Role; Serine; Severity of illness; Signal Pathway; Signal Transduction; Signaling Molecule; Sirolimus; T-Lymphocyte; Testing; Tetrahydrofolates; Therapeutic; Tissues; Tuberculosis; Up-Regulation; Warburg Effect; adaptive immunity; cancer cell; dietary; efficacy testing; experience; folic acid supplementation; hypoxia inducible factor 1; immune activation; immunopathology; improved; in vivo; inhibitor; metabolomics; mitochondrial metabolism; mouse model; novel; nucleotide metabolism; prevent; programs; response; side effect; targeted treatment; transcriptomic profiling; tuberculosis treatment

Abstract The immunometabolism of tuberculosis (TB) offers new opportunities for controlling this deadly infectious disease. We and others have characterized the immunometabolic changes in multiple animal models of TB and found that metabolic remodeling to the HIF-1-mediated Warburg effect is a general response to infection by Mycobacterium tuberculosis, the causative agent of TB. Recently, using multiple approaches that include metabolomics and transcriptomic profiling, we identified novel core metabolic pathways that are found in both Mtb-infected M1-like macrophages and in mouse lungs. These include glutaminolysis and one-carbon metabolism. One-carbon metabolism catabolizes the transfer of serine-derived one-carbon (1C) units to generate methyl-tetrahydrofolate (THF) intermediates that are then utilized for nucleotide synthesis and for methylation reactions through the methionine cycle. One-carbon metabolism is also involved in redox balancing through the generation of NADH/NADPH and of glycine and cysteine for glutathione (GSH) synthesis. We also found that inhibition of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) leads to diminished M1-like polarization that includes dysregulated mitochondrial function and dampened mTORC1/ATF4 signaling in M1- like macrophages. MTHFD2 is a key mitochondrial enzyme of one-carbon metabolism that is encoded by Mthfd2, which is highly induced in Mtb infected M-like macrophages and mouse lungs. Based on these observations, we hypothesize that mitochondrial MTHFD2-mediated, one-carbon metabolism contributes to metabolic remodeling programs of activating immune cells by generating 1C units for nucleotide synthesis and methylation reactions, as well as reducing equivalents and GSH for redox homeostasis. Since TB is often associated with a deficiency of folic acid, the precursor of the 1C carrier THF, we also hypothesize that folic acid deficiency during Mtb infection dampens one-carbon metabolism, leading to diminished activation, differentiation, and effector function of host immune cells. Moreover, since elevated MTHFD2 in vivo is associated with inflammatory disease severity, we further hypothesize that prolonged and elevated expression of one-carbon metabolism contributes to lung pathology at the chronic stage of Mtb infection. To test our hypothesis, in Aim 1, we will delineate how MTHFD2- mediated, one-carbon metabolism regulates immunometabolic properties of M1-like macrophages, mitochondrial biology, serine metabolic pathways, and the mechanism of Mthfd2 upregulation. In Aim 2, we will generate conditional KO mouse strains lacking Mthfd2 in myeloid cells and T cell lineage to delineate the impact of Mthfd2 deficiency on disease progression and immunometabolic properties of immune cells and/or subsets. With Aim 3, we will use a susceptible mouse model of TB to evaluate the effects of folic acid dietary intake on the expression of host immunity to control Mtb infection. We will also define the therapeutic role of inhibitors targeting one-carbon metabolism during anti-TB treatment at chronic stages of the infection. Our study is expected to advance the development of urgently needed host-directed therapies (HDTs) to enhance the ability of immune cells to clear Mtb infection and/or to prevent the development of pathology.

结核病的免疫代谢为控制这一致命疾病提供了新的机会。 传染病我们和其他人已经在多种动物模型中描述了免疫代谢变化的特征 并发现HIF-1介导的瓦尔堡效应的代谢重塑是对结核病的普遍反应， 感染结核分枝杆菌，结核病的病原体。最近，使用多种方法， 包括代谢组学和转录组学分析，我们确定了新的核心代谢途径， Mtb感染的M1样巨噬细胞和小鼠肺中。这些包括氨解和一碳 新陈代谢.一碳代谢分解代谢丝氨酸衍生的一碳（1C）单位转移到 生成甲基-四氢叶酸（THF）中间体，然后将其用于核苷酸合成和用于 甲硫氨酸循环中的甲基化反应。一碳代谢也参与氧化还原平衡 通过生成NADH/NADPH以及甘氨酸和半胱氨酸来合成谷胱甘肽（GSH）。我们也 发现抑制亚甲基四氢叶酸脱氢酶2（MTHFD 2）导致M1样 极化，包括线粒体功能失调和抑制mTORC 1/ATF 4信号转导在M1- 比如巨噬细胞MTHFD 2是由Mthfd 2编码的一碳代谢的关键线粒体酶， 其在Mtb感染的M样巨噬细胞和小鼠肺中被高度诱导。根据这些观察，我们 假设线粒体MTHFD 2介导的一碳代谢有助于代谢重塑 通过产生用于核苷酸合成和甲基化反应的1C单元来激活免疫细胞的程序， 以及用于氧化还原稳态的还原当量和GSH。由于结核病通常与缺乏 叶酸是1C载体THF的前体，我们还假设Mtb期间叶酸缺乏 感染抑制一碳代谢，导致活化、分化和效应子功能减弱 宿主免疫细胞。此外，由于体内MTHFD 2升高与炎性疾病严重程度相关， 我们进一步假设，一碳代谢的延长和升高的表达有助于肺 在结核分枝杆菌感染的慢性阶段的病理。为了验证我们的假设，在目标1中，我们将描述MTHFD 2- 介导的一碳代谢调节M1样巨噬细胞的免疫代谢特性， 线粒体生物学、丝氨酸代谢途径和Mthfd 2上调的机制。在目标2中，我们将 产生在髓样细胞和T细胞谱系中缺乏Mthfd 2的条件性KO小鼠品系，以描述影响 Mthfd 2缺陷对疾病进展和免疫细胞和/或亚群的免疫代谢特性的影响。 在目标3中，我们将使用结核病易感小鼠模型来评估叶酸饮食摄入对 表达宿主免疫力以控制结核分枝杆菌感染。我们还将定义抑制剂的治疗作用 在感染的慢性阶段抗结核治疗期间靶向一碳代谢。我们的研究是 预计将推动迫切需要的宿主导向疗法（HDTs）的发展，以提高 以清除Mtb感染和/或预防病理学的发展。