Metabolic regulation of macrophage function during M. tuberculosis infection

 描述（由申请方提供）：巨噬细胞作为M的宿主细胞具有双重作用。结核病和细胞，主要负责消除感染。细胞因子IFN- γ激活巨噬细胞是对M.结核IFN- γ激活巨噬细胞杀死M.结核在本申请中，我们探索巨噬细胞代谢，IFN- γ激活和M.结核复制通过特定代谢途径的通量影响免疫细胞中的基因表达和分化途径的概念是一个新兴的感兴趣领域。已经发现糖酵解的酶和代谢物影响包括巨噬细胞在内的多种免疫细胞中转录和翻译的特定机制。了解代谢如何影响巨噬细胞功能对于了解利用巨噬细胞作为宿主细胞的病原体如结核分枝杆菌（Mtb）的存活具有重要意义。这项工作的长期目标是了解巨噬细胞中有氧糖酵解如何影响M。结核IFN- γ激活M.结核分枝杆菌参与有氧糖酵解，导致转录因子HIF-1 a的稳定，并且这种应答是基于IFN- γ的M.肺结核感染。在目标1中，我们提出确定所需的特定酶，以支持在M.结核杆菌感染和IFN- γ激活的巨噬细胞，并利用这一知识在基因上操纵M.肺结核感染。在目标2中，我们定义了有氧糖酵解和转录因子HIF-1a的稳定之间的关系，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，在第三个目标中，我们将检验HIF-1a对参与选择性自噬的基因的调节对于基于IFN- γ的M.肺结核感染。如果成功的话，这项工作将为我们理解M.结核病，可以帮助照亮新的免疫疗法的发展。

 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.