cAMP signaling pathways within Mycobacterium tuberculosis

结核分枝杆菌内的 cAMP 信号通路

基本信息

批准号：
8530705
负责人：
Kathleen A McDonough
金额：
$ 32.88万
依托单位：
WADSWORTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8530705
关键词：
Address Adenylate Cyclase Affect Animal Model Antitubercular Agents Bacteria Binding Binding Sites Biological Markers Biology Camping Catabolism Cells Citric Acid Cycle Complex Cues Cyclic AMP Cyclic AMP Receptor Protein Diagnostic Disease Drug Targeting Environment Enzymes Family Gene Expression Gene Expression Regulation Genes Goals Granuloma Health Human Hypoxia Infection Intervention Intoxication Knock-out Metabolic Metabolic Pathway Metabolism Modeling Molecular Molecular Genetics Mus Mutate Mycobacterium tuberculosis Nature Necrosis Operon Pathogenesis Play Propionates Proteins Regulation Regulator Genes Regulon Reporter Reporter Genes Role Second Messenger Systems Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Staging Starvation Succinate Dehydrogenase Systems Biology Therapeutic Tuberculosis Virulence Work chromatin immunoprecipitation deep sequencing global health improved insight macrophage microbial mutant pathogen promoter response second messenger tool transcription factor tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to negatively impact human health on a global scale. The long term goal of this project is to understand the means by which Mtb senses and responds to its host environment during infection, so that improved biomarkers and treatments for TB disease can be developed. Cyclic AMP (cAMP), which is generated from ATP by adenylyl cyclases, is a universal second messenger used by both microbial pathogens and their mammalian hosts to sense and respond to environmental cues. cAMP plays a central role in virulence gene regulation in Mtb and other bacterial pathogens through its allosteric interactions with cAMP receptor protein (CRP)-like transcription factors. Mtb encodes two such transcription factors: CrpMt, which contributes to virulence in a murine model; and Cmr, which regulates Mtb gene expression within macrophages. Previous work has shown that levels of cAMP within Mtb bacteria increase dramatically upon bacterial entry into macrophages, suggesting a role for cAMP in sensing and responding to the intra-macrophage environment. The current project addresses the hypothesis that cAMP signaling contributes to Mtb-host interactions by regulating gene expression within the bacterium in response to environmental conditions. This hypothesis will be addressed in three specific aims. Aim 1 will redefine the CrpMt regulon and its role in Mtb biology during infection at the global, cellular and molecular levels. Aim 2 addresses the role of Cmr in Mtb biology with a focus on its role in regulating propionate metabolism during macrophage infection and within granulomas. Aim 3 addresses the roles of CrpMt and Cmr as co-regulators with other transcription factors, of the espA virulence operon using a combination of molecular, genetic and cellular approaches. Completion of these studies will significantly advance understanding of cAMP's role in Mtb biology, particularly in the context of bacterial sensing and response to host-associated conditions. This information will contribute to the identification of stage-specific biomarkers of infection and new drug targets. The significance of this project is further enhanced by cAMP's established role in regulating virulence in a wide range of important bacterial pathogens, as well as the exceptionally large and unusual network of cAMP-associated signaling proteins in Mtb.

描述（由申请人提供）：结核分枝杆菌（Mtb）是结核病（TB）的病原体，在全球范围内继续对人类健康产生负面影响。该项目的长期目标是了解结核分枝杆菌在感染期间感知和响应宿主环境的方式，以便开发改进的结核病生物标志物和治疗方法。环 AMP (cAMP) 由腺苷酸环化酶从 ATP 产生，是微生物病原体及其哺乳动物宿主用来感知和响应环境信号的通用第二信使。 cAMP 通过与 cAMP 受体蛋白 (CRP) 样转录因子的变构相互作用，在 Mtb 和其他细菌病原体的毒力基因调控中发挥核心作用。 Mtb 编码两种这样的转录因子：CrpMt，它有助于小鼠模型中的毒力； Cmr，调节巨噬细胞内的 Mtb 基因表达。先前的研究表明，结核分枝杆菌细菌内的 cAMP 水平在细菌进入巨噬细胞后急剧增加，这表明 cAMP 在感知和响应巨噬细胞内环境中发挥着重要作用。当前的项目提出了这样的假设：cAMP 信号通过响应环境条件调节细菌内的基因表达，从而促进结核分枝杆菌与宿主的相互作用。这一假设将通过三个具体目标来解决。目标 1 将重新定义 CrpMt 调节子及其在 Mtb 中的作用感染期间的整体、细胞和分子水平的生物学。目标 2 探讨了 Cmr 在 Mtb 生物学中的作用，重点关注其在巨噬细胞感染期间和肉芽肿内调节丙酸代谢的作用。目标 3 使用分子、遗传和细胞方法的组合解决了 CrpMt 和 Cmr 作为 espA 毒力操纵子的其他转录因子的共同调节器的作用。这些研究的完成将显着促进对 cAMP 在 Mtb 生物学中的作用的理解，特别是在细菌感知和对宿主相关条件的反应方面。这些信息将有助于识别特定阶段的感染生物标志物和新的药物靶点。 cAMP 在调节多种重要细菌病原体毒力方面的既定作用，以及 Mtb 中异常庞大且不寻常的 cAMP 相关信号蛋白网络，进一步增强了该项目的重要性。