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

基本信息

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
项目类别：
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

项目摘要

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.

摘要结核病（TB）的免疫代谢为控制这种致命的疾病提供了新的机会。传染病。我们和其他人已经表征了多种动物模型中的免疫代谢变化 TB 的研究发现 HIF-1 介导的 Warburg 效应的代谢重塑是对 TB 的普遍反应结核分枝杆菌（结核病的病原体）感染。最近，采用多种方法包括代谢组学和转录组学分析，我们发现了新的核心代谢途径 Mtb 感染的 M1 样巨噬细胞和小鼠肺部。这些包括谷氨酰胺分解和一碳代谢。一碳代谢分解丝氨酸衍生的一碳 (1C) 单位的转移产生甲基四氢叶酸 (THF) 中间体，然后用于核苷酸合成和通过蛋氨酸循环进行甲基化反应。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 (MTHFD2) 会导致 M1 样蛋白减少极化，包括 M1- 中线粒体功能失调和 mTORC1/ATF4 信号传导减弱像巨噬细胞。 MTHFD2是由Mthfd2编码的一碳代谢的关键线粒体酶，它在 Mtb 感染的 M 样巨噬细胞和小鼠肺部中被高度诱导。根据这些观察，我们假设线粒体 MTHFD2 介导的一碳代谢有助于代谢重塑通过生成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，以及还原当量和谷胱甘肽以实现氧化还原稳态。由于结核病通常与缺乏有关叶酸是 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，导致激活、分化和效应功能减弱宿主免疫细胞。此外，由于体内 MTHFD2 升高与炎症疾病的严重程度相关，我们进一步假设一碳代谢的延长和升高表达有助于肺 Mtb 感染慢性阶段的病理学。为了检验我们的假设，在目标 1 中，我们将描述 MTHFD2- 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 Mthfd2 上调机制。在目标 2 中，我们将生成骨髓细胞和 T 细胞谱系中缺乏 Mthfd2 的条件 KO 小鼠品系，以描述影响 Mthfd2 缺陷对免疫细胞和/或亚群的疾病进展和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膳食摄入量对表达宿主免疫来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慢性阶段的抗结核治疗期间针对一碳代谢。我们的研究是预计将推动迫切需要的宿主导向疗法（HDT）的开发，以增强能力免疫细胞清除 Mtb 感染和/或防止病理发展。