Glutamine metabolism in tuberculosis

摘要 结核分枝杆菌(Mtb)仍然是最成功的人类病原体，在#年造成150万人死亡 2018年。越来越多的证据表明，结核分枝杆菌存活、持续和致病的能力在很大程度上是由于 它能够颠覆宿主对感染的免疫和抗菌反应。的最新进展 免疫代谢研究表明，代谢向糖酵解的转变，也就是Warburg效应，对 免疫细胞的激活和效应功能，以控制感染。然而，这方面的研究有限。 感染巨噬细胞代谢状态的改变对天然巨噬细胞活化和功能的影响 结核病中的获得性免疫。我们的实验室和其他人已经描述了多发性免疫代谢的变化 TB模型，发现对HIF-1介导的Warburg效应的代谢重构是一种普遍的反应 对结核分枝杆菌的感染。通过对结核分枝杆菌感染巨噬细胞免疫代谢特性的详细分析 转录组，代谢组学和治疗的复合治疗，我们发现了新的证据，M1 巨噬细胞感染初期的极化伴随着谷氨酰胺摄取增加和 新陈代谢。鉴于谷氨酰胺代谢的多效性作用，包括来自TCA的无性反应 循环，氧化还原动态平衡，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是M1代谢重塑程序的组成部分 巨噬细胞。基于这些观察，我们假设谷氨酰胺作为重要的碳和 免疫细胞的氮源及其可获得性和新陈代谢对于激活和 宿主先天免疫和获得性免疫对结核分枝杆菌感染的作用。为了检验我们的假设，我们提出了两个 明确的目标。在目标1中，我们将定义谷氨酰胺在调节M1代谢和生理中的作用 巨噬细胞。我们还将破译谷氨酰胺作为碳源和氮源的代谢足迹 用13C(1-13C和5-13C)谷氨酰胺和15N(a-N， 和谷氨酰胺)。在目标2中，我们将描述谷氨酰胺代谢在调节激活中的作用。 使用经过治疗验证的小分子抑制剂治疗先天性和获得性免疫细胞的功能 谷氨酰胺分解途径。我们还将评估是否向感染结核分枝杆菌的动物补充谷氨酰胺 可作为辅助宿主导向疗法(HDTS)的一种可行策略，以增强宿主的抗菌应答 结核小鼠模型中抗结核分枝杆菌感染的免疫细胞。通过阐明谷氨酰胺代谢的影响 关于宿主免疫细胞的功能特性，这项研究将建立结核病免疫代谢的新方面 研究。这项研究的结果将为开发新的附属HDTS开辟新的途径 全球治疗结核病的谷氨酰胺新陈代谢。

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.