Signaling Mechanisms in Vibrio Cholerae Parallel Quorum Sensing Pathways

霍乱弧菌平行群体感应通路中的信号机制

• 批准号: 10579912
• 负责人: Wai-Leung Ng
• 金额: $ 47.97万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579912
• 关键词: Affect; Animals; Bacteria; Behavior; Biochemical; Biological Assay; Cell Communication; Cell Signaling Process; Cell physiology; Cells; Chemicals; Cholera; Chromatography; Communicable Diseases; Competence; Cyclic AMP; Cyclic GMP; Data; Detection; Development; Dinucleoside Phosphates; Disease; Environment; Ethanolamines; Gastrointestinal tract structure; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Health; Human; Infection; Investigation; Knowledge; Life Cycle Stages; Ligand Binding; Ligands; Link; Mediator; Metabolism; Microbial Biofilms; Molecular; Natural Immunity; Pathogenesis; Pathway interactions; Periodicity; Phosphotransferases; Physiological; Population; Predisposition; Process; Production; Proteins; Regulon; Research; Role; Second Messenger Systems; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Structural Models; Structure; System; Techniques; Time; Translating; Vibrio cholerae; Virulence; Virulence Factors; Work; X-Ray Crystallography; combat; design; environmental stressor; follow-up; gene function; gut colonization; host colonization; human pathogen; improved; mutant; novel; novel therapeutics; pandemic disease; pathogen; protein-histidine kinase; quorum sensing; receptor; response; trait; virulence gene; whole animal imaging

Project Summary The human pathogen Vibrio cholerae, the causative agent of the disease cholera, regulates virulence factor production, biofilm formation, competence, and other important processes through quorum sensing (QS), a cell-cell communication mechanism that relies on the production, detection, and response to chemical signal molecules called autoinducers. QS allows bacteria to coordinate population-wide gene expression and function as coordinated groups. We have identified four QS signaling pathways that integrate into the central QS circuit of V. cholerae. Importantly, we found that disruption of these four sensory pathways altogether renders V. cholerae unable to colonize animal hosts. Our data also suggest that ethanolamine and cyclic AMP (cAMP), respectively, are responsible for controlling two of these receptors, CqsR and VpsS. In Aim 1, we will determine how ethanolamine and other related molecules regulate CqsR. In Aim 2, we will determine how cAMP regulates VpsS. In Aim 3, we will define the regulatory hierarchy in the V. cholerae QS circuit. Specifically, we will determine the roles of a recently discovered cyclic dinucleotide called cyclic GMP-AMP in QS gene regulation. Together, our work will not only define the role of QS in V. cholerae pathogenesis, it will also illustrate how integration of multiple signals results in a coherent response in a bacterial cell-cell communication process. It is now well established that QS is employed by many bacterial species to regulate both harmful and beneficial traits. A long standing goal in the field is to develop pro-QS and/or anti-QS molecules to manipulate bacterial group behaviors. Our hope is to harness the knowledge on QS to enable the design of interference strategies that can be translated into new therapies to combat infectious diseases.

项目摘要 人类病原体霍乱弧菌是霍乱的病原体， 毒力因子产生、生物膜形成、感受态和其他重要过程 通过群体感应（QS），一种依赖于生产的细胞间通讯机制， 检测和响应化学信号分子称为autoinducers。QS允许细菌 协调群体范围内的基因表达，并作为协调群体发挥作用。我们有 鉴定了整合到霍乱弧菌中央QS回路中的四种QS信号通路。 重要的是，我们发现这四种感觉通路的破坏共同使V。 不能在动物宿主中繁殖的霍乱。我们的数据还表明，乙醇胺和环 AMP（cAMP）分别负责控制这些受体中的两种，CqsR和VpsS。 在目标1中，我们将确定乙醇胺和其他相关分子如何调节CqsR。在Aim中 2、我们将确定cAMP如何调节VpsS。在目标3中，我们将界定监管层级 在霍乱弧菌QS循环中。具体来说，我们将确定最近发现的一个角色， 环二核苷酸称为环GMP-AMP在QS基因调控中的作用。我们的工作不仅将 为了明确QS在V. cholecystectomy发病机制中的作用，它还将说明如何整合多种 信号导致细菌细胞-细胞通信过程中的相干响应。现在 公认的是，QS被许多细菌物种用来调节有害的和有害的微生物。 有益的性状本领域的长期目标是开发前QS和/或抗QS分子 来操纵细菌的群体行为。我们的希望是利用QS的知识， 设计干预策略，可以转化为新的疗法，以打击传染病 疾病