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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一致命疾病提供了新的机会