Cell-Cell Communicaton in Bacterial Quorum Sensing

描述（由申请人提供）：群体感应是当细胞群体密度超过临界值时，多种细菌物种表现出的复杂的集体行为。由群体感应调节的过程的实例是遗传能力的发展、接合质粒转移、孢子形成和细胞分化、生物膜形成、毒力应答、抗生素、抗微生物肽和毒素的产生以及生物发光。群体感应中的集体行为可以导致生物膜的形成，即包裹在多糖凝胶中的高度组织化和空间结构化的细菌菌落。美国疾病控制中心估计，生物膜导致发达国家65%的感染。生物膜的形成困扰着静脉内、气管内和泌尿管、外科缝合线、导管和隐形眼镜的使用。生物膜可以显示复杂系统的非常复杂的时间和空间自组织行为特征。因此，定量地了解群体感应的机制对于临床上对抗正在发展的传染病是至关重要的。在这里，我们建议调查群体感应的自适应特性的理论，通过随机接种的相互作用的细胞和实验的计算模型的建设，通过调查单细胞和群体的反应在实验模型的群体感应：费氏弧菌。特别是，我们将调查的假设，即双相调节扩散的自诱导剂生产的个别细胞上的本地自诱导剂浓度使群体感应强大的全球和本地的细胞密度的变化。此外，我们将验证预测，双相性质的自动诱导物自动调节允许细胞，以减少高代谢负荷所必需的维持高水平的群体反应。这些假设表明群体感应反应具有高度的适应性和鲁棒性。所提出的模型是一个算法的例子，自下而上的方法，允许考虑到自然噪声和变异性的实验数据的分析。作为该提案的一部分，我们将开发一种新的方法，用于在非常高的细胞密度下分析V.fischeri群体感应，通常不允许分批液体细胞培养。验证后，模型的发展将扩展到包括生物膜形成和生物膜结构的分析，在光的群体感应多物种相互作用。

DESCRIPTION (provided by applicant): Quorum sensing is a complex, collective behavior displayed by a variety of bacterial species when the cell population density exceeds the critical value. Examples of processes modulated by quorum sensing are the development of genetic competence, conjugative plasmid transfer, sporulation and cell differentiation, biofilm formation, virulence response, production of antibiotics, antimicrobial peptides and toxins, and bioluminescence. Collective behavior in quorum sensing can result in the formation of biofilms, highly organized and spatially structured bacterial colonies encased in polysaccharide gels. The U.S. Centers for Disease Control has estimated that biofilms cause 65 percent of infections in the developed world. Biofilm formation plagues the use of intravenous, endotracheal and urinary tubes, surgical sutures, catheters and contact lenses. Biofilms can display very sophisticated temporal and spatial self-organizing behavior characteristic of complex systems. Therefore quantitative understanding of the mechanisms underlying quorum sensing is essential for combating developing infectious diseases in clinic. Here we propose to investigate adaptive properties of quorum sensing both theoretically, by construction of computational model of randomly seeded interacting cells and experimentally, by investigating single cell and population responses in an experimental model of quorums sensing: Vibrio fischeri. In particular, we will investigate the hypothesis that biphasic regulation of diffusible autoinducer production by individual cells on the local autoinducer concentration makes quorum sensing robust to global and local variations in cell density. In addition, we will verify the prediction that biphasic nature of autoinducer autoregulation allows cells to reduce high metabolic load necessary to maintain high level quorum response. These hypotheses suggest high degree of adaptability and robustness in quorum sensing response. The model proposed is an example of an algorithmic, bottom-up approach that allows to take the natural noisiness and variability into account in the analysis of experimental data. As a part of the proposal we will develop a novel method for analysis of V. fischeri quorum sensing at very high cell densities, normally not allowed in the batch liquid cell culture. Following verification, the model development will be extended to include multi-species interaction in biofilm formation and analysis of biofilm structure in light of quorum sensing.