Glutamine metabolism in tuberculosis

结核病中的谷氨酰胺代谢

基本信息

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
项目类别：
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

项目摘要

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 万人死亡 2018. 越来越多的证据表明，结核分枝杆菌的生存、持续和致病能力很大程度上归因于其破坏宿主免疫和对感染的抗菌反应的能力。免疫代谢研究表明，代谢转变为糖酵解，又名瓦尔堡效应，对于然而，免疫细胞的激活和效应功能以控制感染的研究有限。研究受感染巨噬细胞代谢状态的变化如何影响先天和巨噬细胞的激活和功能我们的实验室和其他实验室已经表征了多种结核病的免疫代谢变化。 TB 模型，发现 HIF-1 介导的 Warburg 效应的代谢重塑是一种普遍反应通过使用 Mtb 感染的巨噬细胞的免疫代谢特性进行详细分析。转录组学、代谢组学和治疗性复合治疗，我们发现了 M1 的新证据巨噬细胞感染初期的极化伴随着谷氨酰胺摄取的增加和鉴于谷氨酰胺代谢的多效性作用，包括 TCA 的回补反应。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的摄取和代谢构成了 M1 代谢重塑程序的一个组成部分基于这些观察，我们发现谷氨酰胺的功能与碳一样重要。免疫细胞的氮源及其可用性和代谢对于激活和免疫细胞至关重要宿主对 Mtb 感染的先天免疫和适应性免疫的功能为了检验我们的假设，我们两个提出。具体目标在目标 1 中，我们将定义谷氨酰胺在介导 M1 代谢和生理学中的作用。我们还将破译谷氨酰胺作为碳源和氮源的代谢足迹。使用 13C（1-13C 和 5-13C）谷氨酰胺和 15N（a-N，在目标 2 中，我们将描述谷氨酰胺代谢在介导激活中的作用。和先天性和适应性免疫细胞的功能，使用经过治疗验证的小分子抑制剂我们还将评估是否向 Mtb 感染的动物补充谷氨酰胺。可作为辅助宿主定向治疗 (HDT) 的可行策略，以增强宿主的抗菌反应通过阐明谷氨酰胺代谢的影响，免疫细胞在结核病小鼠模型中抵抗结核分枝杆菌感染。基于宿主免疫细胞的功能特性，这项研究将建立结核病的新免疫代谢方面这项研究的结果将为开发新的辅助 HDT 开辟新的途径。谷氨酰胺代谢在全球范围内治疗结核病。