Manipulating quorum sensing system to control pathogenicity in Vibrio cholerae

描述（由申请人提供）：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，将研究致病菌霍乱弧菌细胞间通讯的过程。霍乱弧菌是霍乱的病原，霍乱是一种严重的腹泻疾病，在发展中国家引起巨大的公共卫生关注。霍乱弧菌的群体感应依赖于细胞外信号分子的产生、释放、检测和反应，这些分子被称为自诱导剂。群体范围内的自诱导剂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剂CAI-1和AI-2激活。CAI-1是显性信号，由膜结合组氨酸传感器激酶CqsS检测，这是本研究的重点。在霍乱弧菌中，群体感应抑制生物膜的形成和毒力因子的产生。因此，激活群体感应的分子（“促群体感应”分子）有可能抑制霍乱弧菌的毒力，并被开发成治疗药物。本研究的目的是定义

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.