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：
9049446
负责人：
Sarah A Stanley
金额：
$ 38.26万
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 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9049446
关键词：
Aerobic Area Autophagocytosis BNIP3L gene CRISPR/Cas technology Cells Cellular Metabolic Process Data Development Dimensions Enzymes Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genome engineering Glycolysis Goals Health Human Immune Immune response Immunity Infection Infection Control Inflammation Mediators Inflammatory Inflammatory Response Interferon Type II Interferons Knowledge Lead Lysosomes Macrophage Activation Mediating Metabolic Metabolic Control Metabolic Pathway Metabolism Methods Molecular Mus Mycobacterium tuberculosis Nitric Oxide Nutrient Pathway interactions Phagosomes Physiological Proteins Public Health Regulation Regulator Genes Research Role Signal Pathway Testing Therapeutic Toll-like receptors Translations Tuberculosis Work aerobic glycolysis base cytokine in vivo innovation interest killings macrophage microbicide novel pathogen programs research study response small hairpin RNA therapeutic vaccine tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Macrophages serve the dual role as the host cell for M. tuberculosis and the cell that is primarily responsible for eliminating infection. Macrophage activation by the cytokine IFN- γ is the cornerstone of effective immune responses to M. tuberculosis. There are still gaps in our understanding of the molecular mechanisms by which IFN- γ activates macrophages to kill M. tuberculosis. In this application we explore connections between macrophage metabolism, IFN- γ activation and control of M. tuberculosis replication. The concept that flux through specific metabolic pathways impacts gene expression and pathways of differentiation in immune cells is an emerging area of interest. Enzymes and metabolites of glycolysis have been found to impact specific mechanisms of transcription and translation in multiple immune cells including macrophages. Understanding how metabolism impacts macrophage function has important consequences for understanding the survival of pathogens such as Mycobacterium tuberculosis (Mtb) that exploit macrophages as a host cell. The long term- goal of this work is to understand how aerobic glycolysis in macrophages impacts infection with M. tuberculosis. We have found that IFN- γ activated macrophages infected with M. tuberculosis engage in aerobic glycolysis resulting in stabilization of the transcription factor HIF-1a and that this response is required for IFN- γ based control of M. tuberculosis infection. In aim 1 we propose to identify specific enzymes that are required to support enhanced glycolytic flux observed in M. tuberculosis infected and IFN- γ activated macrophages, and to use this knowledge to genetically manipulate glycolysis during M. tuberculosis infection. In aim 2 we define the relationship between aerobic glycolysis and stabilization of the transcription factor HIF-1a, and identify macrophage-signaling pathways that are controlled by HIF-1a and/or aerobic glycolysis. Finally, in aim three we will test the hypothesis that HIF-1a regulation of genes that participate in selective autophagy is important for IFN- γ based control of M. tuberculosis infection. If successful, the proposed work will open up a new dimension to our understanding of immune control of M. tuberculosis that can help illuminate the development of novel immune therapeutics.

描述（由申请人提供）：巨噬细胞作为结核分枝杆菌的宿主细胞和主要负责消除感染的细胞发挥双重作用，细胞因子IFN-γ激活巨噬细胞是对结核分枝杆菌有效免疫反应的基石。我们对 IFN-γ 激活巨噬细胞杀死结核分枝杆菌的分子机制的理解仍然存在差距。在本应用中，我们探讨了巨噬细胞代谢、 IFN-γ 的激活和结核分枝杆菌复制的控制通过特定代谢途径影响基因表达和免疫细胞分化途径的概念是一个新兴的兴趣领域。已发现糖酵解的酶和代谢物会影响特定的代谢途径。了解代谢如何影响巨噬细胞功能对于了解以巨噬细胞为宿主细胞的结核分枝杆菌 (Mtb) 等病原体的生存具有重要意义。这项工作的长期目标是了解巨噬细胞中的有氧糖酵解如何影响结核分枝杆菌的感染。我们发现感染结核分枝杆菌的 IFN-γ 激活的巨噬细胞参与有氧糖酵解，从而导致转录因子 HIF- 的稳定。 1a 并且这种反应是基于 IFN-γ 的结核分枝杆菌感染控制所必需的。在目标 1 中，我们建议识别支持增强所需的特定酶。在结核分枝杆菌感染和 IFN-γ 激活的巨噬细胞中观察到的糖酵解通量，并利用这些知识在结核分枝杆菌感染期间对糖酵解进行基因操纵。在目标 2 中，我们定义了有氧糖酵解与转录因子 HIF-1a 稳定之间的关系。并确定由 HIF-1a 和/或有氧糖酵解控制的巨噬细胞信号通路。最后，在目标三中，我们将检验以下假设： HIF-1a 对参与选择性自噬的基因的调节对于基于 IFN-γ 的结核分枝杆菌感染控制非常重要，如果成功，这项工作将为我们理解结核分枝杆菌的免疫控制开辟新的维度。阐明新型免疫疗法的发展。