Manipulating quorum sensing system to control pathogenicity in Vibrio cholerae

操纵群体感应系统控制霍乱弧菌的致病性

• 批准号: 8749228
• 负责人: Alice Kyungsun Min
• 金额: $ 4.77万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2019-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8749228
• 关键词: Acute; Agonist; Amino Acids; Bacteria; Behavior; Binding; Biochemical; Biological Assay; Cell Communication; Cell Signaling Process; Cell physiology; Cells; Cholera; Communities; Detection; Development; Diarrhea; Digestive System Disorders; Disease; Genetic; Goals; Human; In Vitro; Infection; Ligands; Maps; Membrane; Microbial Biofilms; Molecular; Mutagenesis; N-(3-oxohexanoyl)-3-aminodihydro-2(3H)-furanone; Pathogenicity; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Population Density; Production; Public Health; Series; Signal Transduction; Signaling Molecule; Source; Specificity; Stomach; Structure; Synthesis Chemistry; System; Therapeutic; Vibrio; Vibrio cholerae; Virulence; Virulence Factors; extracellular; genetic analysis; in vivo; insight; interest; novel therapeutics; pathogen; pathogenic bacteria; public health relevance; quorum sensing; receptor; research study; response; sensor; sensor histidine kinase

DESCRIPTION (provided by applicant): The overarching goal of this study is to understand the molecular mechanisms underpinning bacterial collective behaviors required for causing acute gastric infections in humans. To explore this, quorum sensing, the process of cell-cell communication in the pathogenic bacterium Vibrio cholerae will be studied. V. cholerae is the etiological agent of the disease cholera, a severe diarrheal condition that is a source of enormous public health concern in the developing world. Quorum sensing in V. cholerae depends on the production, release, detection, and response to extracellular signaling molecules called autoinducers. Group-wide detection of autoinducers allows V. cholerae to synchronously alter its behavior in response to changes in the population density and species composition of the vicinal bacterial community. In V. cholerae, quorum sensing is activated by two autoinducers, CAI-1 and AI-2. CAI-1, the dominant signal, is detected by the membrane-bound histidine sensor kinase, CqsS, and these are the focus of this study. In V. cholerae, quorum sensing represses biofilm formation and virulence factor production. Thus, molecules that activate quorum sensing ("pro-quorum sensing" molecules) have the potential to repress virulence in V. cholerae and to be developed into therapeutics. The goal of this study is to define the molecular mechanism by which specific molecules are recognized by the CqsS receptor and determine how they elicit the quorum sensing response. Particularly interesting are ligand- receptor interactions between CqsS and the recently discovered CqsS agonist called WYZ301. WYZ301 is structurally distinct from CAI-1 and yet it potently agonizes quorum sensing. Studying new molecules, such as WYZ301, should greatly enhance the understanding of how CqsS interacts with ligands to generate the quorum sensing response. More generally, these studies will contribute to the development of novel therapeutics for V. cholerae, closely related pathogenic vibrios, as well as other diarrhea-causing bacteria that use quorum sensing for collective behaviors, including virulence.

描述（由申请人提供）：本研究的总体目标是了解引起人类急性胃感染所需的细菌集体行为的分子机制。为了探索这一点，我们将研究致病菌霍乱弧菌中细胞间通讯的群体感应过程。霍乱弧菌是霍乱病的病原体，霍乱是一种严重的腹泻病，是发展中国家巨大的公共卫生问题的根源。霍乱弧菌的群体感应取决于称为自诱导剂的细胞外信号分子的产生、释放、检测和响应。群体范围内的自诱导剂检测使霍乱弧菌能够同步改变其行为，以响应邻近细菌群落的种群密度和物种组成的变化。在霍乱弧菌中，群体感应由两种自诱导剂 CAI-1 和 AI-2 激活。 CAI-1 是主要信号，由膜结合组氨酸传感器激酶 CqsS 检测，这些是本研究的重点。在霍乱弧菌中，群体感应抑制生物膜形成和毒力因子产生。因此，激活群体感应的分子（“原群体感应”分子）有可能抑制霍乱弧菌的毒力并被开发成治疗药物。本研究的目标是定义 CqsS 受体识别特定分子并决定它们如何引发群体感应反应的分子机制。特别有趣的是 CqsS 和最近发现的称为 WYZ301 的 CqsS 激动剂之间的配体-受体相互作用。 WYZ301 在结构上与 CAI-1 不同，但它能有效地抑制群体感应。研究新分子（例如 WYZ301）应该会极大地增强对 CqsS 如何与配体相互作用以产生群体感应响应的理解。更一般地说，这些研究将有助于开发针对霍乱弧菌、密切相关的致病性弧菌以及其他利用群体感应进行集体行为（包括毒力）的腹泻细菌的新疗法。