Cyclic AMP secretion mechanisms in M. tuberculosis

结核分枝杆菌中的环磷酸腺苷分泌机制

• 批准号: 9332666
• 负责人: Kathleen A McDonough
• 金额: $ 25.58万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332666
• 关键词: Address; Adenylate Cyclase; Affect; Antigens; Bacteria; Bacterial Genes; Binding; Biochemical; Biological; Biological Assay; Biological Markers; Biology; Bioluminescence; Cell Membrane Permeability; Cell membrane; Cells; Cues; Cyclic AMP; Cyclic Nucleotides; Cytoplasm; Cytosol; Disease; Disease Progression; Environment; Epidemic; Fibrinogen; Fluorescence; Future; Gene Expression Regulation; Genes; Goals; Immune response; Infection; Intervention; Knowledge; Mediating; Microscopy; Molecular Genetics; Mutagenesis; Mycobacterium tuberculosis; Nature; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Pilot Projects; Play; Process; Proteins; Reporter; Research Infrastructure; Resources; Role; Second Messenger Systems; Signal Transduction; Signaling Molecule; Testing; Time; Tuberculosis; Virulence; Work; base; genetic approach; global health; immunocytochemistry; improved; innovation; loss of function; macrophage; microbial; mutant; pathogen; response; specific biomarkers; tool

Abstract Control of the current tuberculosis (TB) epidemic will require better understanding of the biological mechanisms used by Mycobacterium tuberculosis (Mtb) to sense, respond to and manipulate its host environment during infection. Cyclic AMP (cAMP) is a universal signal molecule 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 several important bacterial pathogens, and regulates many aspects of mammalian host biology, including the immune response. Many bacteria, including Mtb, exploit this common signaling molecule by elevating cAMP levels in their host cells as a pathogenic strategy. Levels of cAMP within Mtb bacteria increase dramatically upon bacterial entry into macrophages, and some of this cAMP is secreted into host macrophages to alter the course of infection. The scientific premise for this proposal is that the cAMP export from Mtb bacteria into macrophages contributes to TB pathogenesis, but the mechanisms underlying cAMP secretion and its specific activities within the host cell are not known. We hypothesize that cyclic AMP secretion from the bacterium is regulated in response to environmental conditions, and that Mtb actively facilitates access of secreted cAMP to the cytoplasm of infected host macrophages to manipulate the host response to infection. Major goals of this proposal are to identify bacterial factors that i) control secretion of cAMP from Mtb bacteria, and ii) affect cytoplasmic access of this Mtb-secreted cAMP during macrophage infection. Knowledge of these factors will provide a critical basis for understanding the mechanisms underlying both cAMP export processes and their specific roles in Mtb pathogenesis, with the long term potential for identification of new TB interventions and/or biomarkers of disease progression.

抽象的 控制当前的结核病（TB）流行需要更好地了解其生物学原理 结核分枝杆菌 (Mtb) 用于感知、响应和操纵宿主的机制 感染时的环境。环磷酸腺苷 (cAMP) 是一种通用信号分子，被微生物和微生物所使用。 病原体及其哺乳动物宿主感知环境信号并做出反应。 cAMP 发挥着中枢作用 在几种重要细菌病原体的毒力基因调节中发挥作用，并调节细菌病原体的许多方面 哺乳动物宿主生物学，包括免疫反应。许多细菌，包括 Mtb，都利用这一点 常见的信号分子通过提高宿主细胞中的 cAMP 水平作为致病策略。级别 当细菌进入巨噬细胞时，结核分枝杆菌细菌内的 cAMP 急剧增加，其中一些 cAMP 分泌到宿主巨噬细胞中以改变感染过程。这样做的科学前提 提议认为，结核分枝杆菌细菌向巨噬细胞输出 cAMP 有助于结核病发病机制，但是 cAMP 分泌的机制及其在宿主细胞内的具体活性尚不清楚。我们 假设细菌的环 AMP 分泌受到环境调节的调节 条件下，并且 Mtb 主动促进分泌的 cAMP 进入受感染宿主的细胞质 巨噬细胞操纵宿主对感染的反应。该提案的主要目标是确定 细菌因素 i) 控制 Mtb 细菌分泌 cAMP，以及 ii) 影响其细胞质进入 巨噬细胞感染期间 Mtb 分泌的 cAMP。了解这些因素将提供关键基础 了解 cAMP 输出过程的潜在机制及其在 Mtb 中的具体作用 发病机制，具有确定新的结核病干预措施和/或结核病生物标志物的长期潜力 疾病进展。