Combined multiscale modeling and experimental study of bacterial swarming

描述（由申请人提供）：自然和临床环境中的大多数细菌以表面附着生物膜的形式生长，生物膜是自组装成封闭基质的细菌群落。表面运动的一种模式，称为群集，在细胞中观察到，通过旋转鞭毛、分泌粘液和收缩IV型皮利来推动。由于蜂群的调节是由复杂多变的多尺度事件组合控制的，因此对蜂群的研究尤为重要。当群集时，细菌群落可以以大规模的协调模式移动，超过单个细菌的大小，数量级取决于单个细胞的基因表达，水合环境中存在的化学信号的感测，以及影响附着的细菌细胞的物理特性。迄今为止，细菌运动性的最先进的建模工作集中在单一水平或尺度上，例如，基因组/蛋白质组、细胞和群体。 铜绿假单胞菌是一种机会性人类病原体，可引起易感个体的皮肤、眼睛、肺和胃肠道感染。我们建议通过开发和整合从微观到宏观尺度的模型来研究铜绿假单胞菌群集，以分析细菌运动与实验室实验。尺度之间的整合将导致对生物现象的普遍或一般特征以及不同尺度的同步过程如何相互作用的更深入的理解。这项研究的主要假设是，细菌协调细胞密度和合作，以最大限度地提高表面运动，这需要这些细胞同化人口，营养和物理线索。由于细胞相互作用的识别在实验上非常困难，我们将使用多尺度模型来进行预测模拟，描述可能控制群集的复杂细菌相互作用。对细菌模式形成机制的研究将有助于确定细胞之间的关键相互作用，描述细菌表面定殖的机制，并为工程和控制表面上的细菌生长提供知识。 这项工作的一个关键方面将是将计算机模拟获得的预测与实验观察进行比较，以校准模型，并使用该模型生成新的生物学假设进行实验测试。特别感兴趣的是要检查的运动模式，表面液体的性质，和细胞-细胞的物理相互作用所需的铜绿假单胞菌群集的影响。我们提出的迭代方法将使用多尺度模型模拟和实验室实验来描述群集的变化与运动和鼠李糖脂生产的改变，结合实验室检查的同基因突变体缺乏某些运动模式或鼠李糖脂生产。这项工作将使我们能够确定细菌如何通过协调它们的运动和随着时间的推移产生鼠李糖脂来有效地在表面上定居。

DESCRIPTION (provided by applicant): Most bacteria in natural and clinical settings grow as surface-attached biofilms, which are bacterial communities that have self-assembled into an encased matrix. One mode of surface motility, called swarming, is observed in cells that are propelled by rotating flagella, by the secretion of slime, and by retracting type IV pili. Study of swarming is particularly important because its regulation is controlled by combination of complex and variable multi-scale events. While swarming, a bacterial community may move in a large-scale coordinated pattern exceeding the size of individual bacterium by orders of magnitude depending upon the gene expression of individual cells, the sensing of chemical signals present in a hydrating environment, and the physical characteristics influencing the attached bacterial cells. To date, the most advanced modeling efforts of bacterial motility have focused on single levels or scales, e.g., genomic/proteomic, cellular and population. The bacterium Pseudomonas aeruginosa is an opportunistic human pathogen that causes skin, eye, lung, and gastrointestinal infections in susceptible individuals. We propose to study P. aeruginosa swarming by developing and integrating models from micro-scales to macro-scales to analyze bacterial motility in concert with laboratory experiments. Integration between scales will lead to a much deeper understanding of the universal or generic features of biological phenomena and how simultaneous processes at different scales interact. The main hypothesis of this proposed research is that bacteria coordinate cell density and cooperation to maximize surface motility which requires assimilation of population, nutrient, and physical cues by these cells. Because identification of cell interactions is extremely difficult experimentally, we will use multi-scale models to perform predictive simulations describing complex bacterial interactions that potentially control swarming. Study of the mechanisms of bacterial pattern formation will help identify the key interactions between cells, describe a mechanism of bacterial surface colonization, and provide knowledge for engineering and controlling bacterial growth on surfaces. A key aspect of this work will be to compare the predictions obtained in silico with experimental observations to calibrate the model and use the model to generate new biological hypotheses to be tested experimentally. Of particular interests to be examined are the influence of motility patterns, surface liquid properties, and cell-cell physical interactions required for Pseudomonas aeruginosa swarming. Our proposed iterative approach will use multiscale model simulations and laboratory experiments to describe variations to swarming with alterations to motility and rhamnolipid production in combination with laboratory examination of isogenic mutants deficient in certain motility modes or rhamnolipid production. This work will allow us to determine how bacteria efficiently colonize surfaces by coordinating their motion and rhamnolipid production over time.