Glutamine metabolism in tuberculosis

结核病中的谷氨酰胺代谢

• 批准号: 10287785
• 负责人: Lanbo Shi
• 金额: $ 21.27万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-06 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287785
• 关键词: Affect; Alveolar Macrophages; Animals; Antibiotics; Antigen-Presenting Cells; Arginine; Bioenergetics; Biological Assay; Bone Marrow; Carbon; Cause of Death; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Citric Acid Cycle; Communicable Diseases; Coupled; Dendritic Cells; Development; Disease; Drug resistance; Drug resistance in tuberculosis; Enzyme-Linked Immunosorbent Assay; Epidemic; Failure; Fishes; Flow Cytometry; Gene Expression; Glutamate Metabolism Pathway; Glutaminase; Glutamine; Glycolysis; Granuloma; Growth; HIV; Homeostasis; Image; Immune; Immune response; Immunity; Immunofluorescence Immunologic; Infection; Infection Control; Isotope Labeling; Isotopes; Laboratories; Lipids; Lung; Mass Fragmentography; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; NADP; Natural Immunity; Nitrogen; Outcome Study; Oxidation-Reduction; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Physiological; Physiology; Preventive; Proliferating; Property; RNA; Reaction; Regimen; Regulation; Research; Role; Source; Supplementation; System; Testing; Therapeutic; Therapeutic Uses; Tracer; Translating; Treatment outcome; Tuberculosis; Up-Regulation; Warburg Effect; adaptive immunity; aerobic glycolysis; antimicrobial; base; co-infection; defense response; draining lymph node; experimental study; human pathogen; hypoxia inducible factor 1; immune function; improved; in vivo; inhibitor/antagonist; innate immune function; macrophage; metabolomics; mouse model; novel; novel therapeutic intervention; nucleotide metabolism; pathogen; programs; resistant strain; response; single molecule; small molecule; small molecule inhibitor; stable isotope; targeted treatment; transcriptomics; tuberculosis immunity; uptake

Abstract Mycobacterium tuberculosis (Mtb) remains the most successful human pathogen, causing 1.5 million deaths in 2018. Accumulating evidence suggests that Mtb’s ability to survive, persist and cause disease is largely due to its ability to subvert the host immune and antimicrobial response to infection. Recent advances in immunometabolism studies have shown that a metabolic shift to glycolysis, aka the Warburg effect, is critical for the activation and effector functions of immune cells to control the infection. However, there are limited studies on how the change of metabolic state of infected macrophages affects the activation and function of innate and adaptive immunity in TB. Our laboratory and others have characterized the immunometabolic changes in multiple model of TB and found that the metabolic remodeling to the HIF-1-mediated Warburg effect is a general response to Mtb infection. Through detailed analysis of immunometabolic properties of Mtb-infected macrophages using transcriptomics, metabolomics and therapeutic compound treatment, we discovered novel evidence that M1 polarization at initial stage of macrophage infection is accompanied by increased glutamine uptake and metabolism. Given the pleiotropic roles of glutamine metabolism, including anaplerotic reactions from the TCA cycle, redox homeostasis, and synthesis of nucleotides and NADPH, findings from our studies suggest that glutamine uptake and metabolism constitute an integral component of metabolic remodeling program of M1 macrophages. Based on these observations, we hypothesize that glutamine functions as important carbon and nitrogen source for immune cells and that its availability and metabolism are essential for the activation and function of host innate and adaptive immunity against Mtb infection. To test our hypothesis, we propose two Specific Aims. In Aim 1, we will define the role of glutamine in mediating the metabolism and physiology of M1 macrophages. We will also decipher the metabolic footprints of glutamine as carbon and nitrogen source during M1 polarization using stable isotope tracing metabolomics with 13C (1-13C and 5-13C) glutamine and 15N (a-N, and g-N) glutamine. In Aim 2, we will characterize the role of glutamine metabolism in mediating the activation and functions of innate and adaptive immune cells using therapeutically validated small molecule inhibitor for glutaminolysis pathway. We will also evaluate whether supplementation of glutamine to Mtb-infected animals can serve as a viable strategy of adjunct host directed therapies (HDTs) to boost antimicrobial response of host immune cells against Mtb infection in a mouse model of TB. By elucidating the effects of glutamine metabolism on the functional property of host immune cells, this study will establish a novel immunometabolic aspect of TB research. Outcomes of this study will open new avenues for the development of new adjunct HDTs by targeting glutamine metabolism to treat TB worldwide.

抽象的 结核分枝杆菌（MTB）仍然是最成功的人类病原体，导致150万死亡 2018年。积累证据表明，MTB生存，持久和引起疾病的能力在很大程度上是由于 它可以颠覆宿主免疫和对感染的抗菌反应的能力。最近的进步 免疫代谢研究表明，向糖酵解的代谢转变，也就是沃伯格效应，对 免疫细胞控制感染的激活和效应功能。但是，研究有限 关于感染巨噬细胞的代谢状态的变化如何影响先天和功能的激活和功能 TB中的自适应免疫史。我们的实验室和其他实验室表征了多个的免疫代谢变化 结核病模型，发现对HIF-1介导的Warburg效应的代谢重塑是一种一般反应 到MTB感染。通过使用MTB感染巨噬细胞的免疫代谢特性的详细分析 转录组学，代谢组学和治疗化合物治疗，我们发现了M1的新证据 巨噬细胞感染初始阶段的极化是通过增加谷氨酰胺的吸收和 代谢。鉴于谷氨酰胺代谢的多效性作用，包括来自TCA的变性反应 循环，氧化还原稳态以及核苷酸和NADPH的合成，我们的研究结果表明 谷氨酰胺摄取和代谢构成了M1代谢重塑程序的组成部分 巨噬细胞。基于这些观察结果，我们假设谷氨酰胺起着重要的碳和 免疫细胞的氮来源，其可用性和代谢对于激活和 宿主先天和适应性免疫学针对MTB感染的功能。为了检验我们的假设，我们提出了两个 具体目标。在AIM 1中，我们将定义谷氨酰胺在介导M1的新陈代谢和生理学中的作用 巨噬细胞。我们还将解读谷氨酰胺作为碳和氮源的代谢足迹 使用稳定的同位素跟踪代谢组学的M1极化，具有13C（1-13C和5-13C）谷氨酰胺和15N（a-n， 和G-N）谷氨酰胺。在AIM 2中，我们将表征谷氨酰胺代谢在介导激活中的作用 以及使用热验证的小分子抑制剂的先天和适应性免疫小球的功能 谷氨酰胺溶解途径。我们还将评估是否补充谷氨酰胺为MTB感染的动物 可以用作辅助宿主定向疗法（HDTS）的可行策略，以增强宿主的抗菌反应 在TB的小鼠模型中，免疫细胞针对MTB感染。通过阐明谷氨酰胺代谢的影响 关于宿主免疫细胞的功能性能，本研究将建立一个新的TB免疫代谢方面 研究。这项研究的结果将通过靶向开发新的HDT开发新的途径 谷氨酰胺代谢以治疗全球结核病。