Manipulating quorum sensing system to control pathogenicity in Vibrio cholerae

描述（由申请方提供）：本研究的总体目标是了解导致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，群体感应，在致病性细菌霍乱弧菌的细胞间通讯的过程将进行研究。霍乱弧菌是霍乱的病原体，霍乱是一种严重的霍乱病症，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依赖于对细胞外信号分子（称为自诱导物）的产生、释放、检测和应答。群体范围内的自诱导物的检测允许霍乱弧菌同步改变其行为，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物CAI-1和AI-2激活。CAI-1，占主导地位的信号，检测膜结合组氨酸传感器激酶，CqsS，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（“促群体感应”分子）具有抑制霍乱弧菌毒力的潜力，并被开发成治疗剂。本研究的目的是确定 CqsS受体识别特定分子的分子机制，并决定它们如何引发群体感应反应。特别令人感兴趣的是CqsS和最近发现的CqsS激动剂WYZ 301之间的配体-受体相互作用。WYZ 301在结构上与CAI-1不同，但它有效地刺激了群体感应。研究新的分子，如WYZ 301，应该大大提高了对CqsS如何与配体相互作用以产生群体感应反应的理解。更一般地说，这些研究将有助于开发新的治疗方法，用于霍乱弧菌，密切相关的致病弧菌，以及其他使用群体感应进行集体行为（包括毒力）的引起霍乱的细菌。

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.