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; 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）流行将需要更好地了解生物学 结核分枝杆菌使用的机制（MTB）感知，应对和操纵其宿主 感染期间的环境。环状AMP（CAMP）是两个微生物使用的通用信号分子 病原体及其哺乳动物宿主感知并应对环境线索。营地扮演中央 在几种重要细菌病原体中的毒力基因调节中的作用，并调节 哺乳动物宿主生物学，包括免疫反应。包括MTB在内的许多细菌都利用了这一点 通用信号分子通过将宿主细胞中的cAMP水平提升为致病策略来提高cAMP水平。水平 在细菌进入巨噬细胞时，MTB细菌内的扎营会大大增加，其中一些 营地被分泌到宿主巨噬细胞中，以改变感染过程。科学前提 提议是从MTB细菌出口到巨噬细胞会导致TB发病机理，但 尚不清楚宿主细胞中营地分泌的基础机制及其在宿主细胞中的特定活性。我们 假设细菌的环状AMP分泌受到环境的调节 条件，MTB积极促进分泌营地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细菌的CAMP分泌，ii）影响了细胞质的进入 巨噬细胞感染期间MTB分泌的营地。对这些因素的了解将提供关键的基础 了解cAMP出口过程及其在MTB中的特定作用的基础机制 发病机理，长期鉴定新的结核病干预措施和/或生物标志物的长期潜力 疾病进展。