Metabolic regulation of macrophage function during M. tuberculosis infection

结核分枝杆菌感染期间巨噬细胞功能的代谢调节

基本信息

批准号：
10626926
负责人：
Sarah A Stanley
金额：
$ 38.75万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-10 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626926
关键词：
Anti-Inflammatory Agents Bacteria Bacterial Infections Biological Models CD4 Positive T Lymphocytes Carrier Proteins Cell membrane Cells Cues Data Development Ensure Equilibrium Feedback Funding Gene Expression Genes Goals Growth Hypoxia Inducible Factor Immune Immune response Immunity Immunotherapeutic agent Individual Infection Infection Control Inflammation Inflammatory Response Interferon Type II Interleukin-1 beta Knowledge Link Macrophage Macrophage Activation Mediating Membrane Metabolic Metabolic Pathway Metabolism Mus Mycobacterium tuberculosis Myeloid Cells NOS2A gene Nitric Oxide Patients Persons Predisposition Production Proteins Public Health Regulation Reporting Research Role Series Signal Transduction System Testing Tuberculosis Vaccines Work aerobic glycolysis antimicrobial bactericide cytokine experimental study in vivo microbicide novel novel therapeutics novel vaccines pathogen pathogenic bacteria programs response solute therapeutic development transcription factor

项目摘要

Project Summary Mycobacterium tuberculosis (Mtb) infects 2 billion people worldwide, and kills more people every year than any other single pathogen. Most people infected with Mtb are able to contain infection for their lifetimes, suggesting the existence of immune mechanisms that can successfully control infection. Identifying these mechanisms is crucial for the development of therapeutics that can bolster immunity in patients with insufficient immunity. Macrophages serve the dual role as both the host cell for Mtb infection, and the cell that is primarily responsible for controlling infection by activating microbicidal mechanisms that effectively kill bacteria. In addition, macrophages influence the inflammatory response to infection by producing both pro-and anti- inflammatory factors. The long-term goal of this project is to understand how macrophage metabolism influences both antimicrobial activity and the regulation of inflammation. Our previous work centered around activation of macrophages by IFN-γ, a cytokine that is critical for immune control of Mtb. We found that an immuno-metabolic loop linking aerobic glycolysis, nitric oxide, and the transcription factor HIF-1α is crucial for both antimicrobial control and regulating the balance of inflammation in macrophages infected ex vivo. In addition, we demonstrated that HIF-1α in macrophages in essential for control of infection in mice. However, it remains unclear whether the importance of HIF-1α and nitric oxide in vivo result from cell intrinsic control by macrophages, regulation of inflammation, or both. Furthermore, recent data from several labs has suggested that IFN-γ, while clearly important, may not be the only factor required for macrophage-based control of infection in vivo. Indeed, several groups have reported that CD4 T cells can also mediate IFN-γ independent control of infection in vivo. We have developed an ex vivo culture system that recapitulates CD4 T cell dependent but IFN-γ independent control of infection, which provides a model system for mechanistic studies. Intriguingly, our preliminary data suggest that macrophages activated by IFN-γ independent mechanisms activate aerobic glycolysis and HIF-1α without producing NO. Finally, very little is known about how macrophages support large scale changes in metabolism via regulated metabolite transport. Here we proposed to further our understanding of both IFN-γ dependent and independent macrophage based control of Mtb infection in three aims: 1) Determine the importance of NO/HIF-1α for cell intrinsic control of Mtb infection in vivo 2) Demonstrate that IFN-γ independent control of Mtb infection requires aerobic glycolysis and HIF-1α 3) Demonstrate that solute carrier proteins play a role in regulating HIF-1α dependent control of infection by supporting metabolite transport across cell membranes.

项目概要结核分枝杆菌 (Mtb) 感染全球 20 亿人，每年造成的死亡人数比任何国家都多其他单一病原体。大多数感染 Mtb 的人能够终生抑制感染。能够成功控制感染的免疫机制的存在是。对于开发能够增强免疫力不足患者免疫力的疗法至关重要。巨噬细胞具有双重作用，既作为 Mtb 感染的宿主细胞，又作为主要的细胞。负责通过激活有效杀死细菌的杀菌机制来控制感染。此外，巨噬细胞通过产生促和抗炎症反应来影响感染的炎症反应。该项目的长期目标是了解巨噬细胞如何代谢。影响抗菌活性和炎症调节。 IFN-γ 激活巨噬细胞，IFN-γ 是一种对 Mtb 免疫控制至关重要的细胞因子。连接有氧糖酵解、一氧化氮和转录因子 HIF-1α 的免疫代谢环对于抗菌控制和调节离体感染的巨噬细胞的炎症平衡。此外，我们证明巨噬细胞中的 HIF-1α 对于控制小鼠感染至关重要。目前尚不清楚 HIF-1α 和一氧化氮在体内的重要性是否来自于细胞内在控制此外，几个实验室的最新数据表明，巨噬细胞、炎症调节或两者兼而有之。 IFN-γ虽然显然很重要，但可能不是基于巨噬细胞的控制所需的唯一因素事实上，多个研究小组已经报道 CD4 T 细胞也可以独立介导 IFN-γ。我们开发了一种可概括 CD4 T 细胞的离体培养系统。依赖但独立于 IFN-γ 的感染控制，为机制研究提供了模型系统。有趣的是，我们的初步数据表明巨噬细胞由 IFN-γ 独立机制激活激活有氧糖酵解和 HIF-1α 而不产生 NO 最后，我们对如何激活有氧糖酵解和 HIF-1α 知之甚少。巨噬细胞通过调节代谢物运输来支持新陈代谢的大规模变化。提议进一步我们对基于 IFN-γ 依赖和独立巨噬细胞的控制的理解 Mtb 感染的三个目标： 1) 确定 NO/HIF-1α 对于 Mtb 感染的细胞内在控制的重要性体内 2) 证明 IFN-γ 独立控制 Mtb 感染需要有氧糖酵解和 HIF-1α 3) 证明溶质载体蛋白在调节 HIF-1α 依赖性感染控制中发挥作用支持代谢物跨细胞膜运输。