Cell-Cell Communicaton in Bacterial Quorum Sensing

描述（由申请人提供）：群体感应是一种复杂的集体行为，当细胞种群密度超过临界值时，多种细菌会表现出这种行为。群体感应调节的过程包括遗传能力的发展、结合质粒转移、孢子形成和细胞分化、生物膜形成、毒力反应、抗生素、抗菌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的细菌菌落。美国疾病控制中心估计，发达国家65%的感染是由生物膜引起的。生物膜的形成困扰着静脉、气管和尿管、外科缝合线、导尿管和隐形眼镜的使用。生物膜可以表现出复杂系统非常复杂的时空自组织行为特征。因此，对群体感应机制的定量理解对于临床对抗发展中的传染病至关重要。在这里，我们提出从理论上研究群体感应的适应性，通过构建随机种子相互作用细胞的计算模型，并通过实验研究群体感应实验模型：费氏弧菌的单细胞和群体响应。特别是，我们将研究单个细胞对局部自诱导剂浓度的扩散性自诱导剂产生的双相调节，使群体感应对细胞密度的全局和局部变化具有鲁棒性。此外，我们将验证自诱导剂自调节的双相性质允许细胞减少维持高水平群体反应所必需的高代谢负荷的预测。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在实验数据分析中考虑自然噪声和可变性。作为提案的一部分，我们将开发一种在非常高的细胞密度下分析V. fischeri群体感应的新方法，通常不允许在批量液体细胞培养中使用。在验证之后，模型的发展将扩展到包括生物膜形成中的多物种相互作用和群体感应下的生物膜结构分析。

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.