From cell-to-cell heterogeneity to collective behaviors in bacterial biofilms

项目总结 细菌生物膜是由自身产生的聚合物基质粘合在一起的细菌群落。 它们几乎存在于地球上的每一个环境中，是大多数医院传播的 感染。这些依附社区对抗生素高度耐受，他们的极端 弹性不能仅仅归因于药物分子不能穿透生物膜 矩阵。已经清楚的是，生物膜中的紧急多细胞行为赋予了独特的 生存策略。近年来，我们已经了解了基因调控的详细机制。 和单个细菌细胞的表型异质性，但我们既没有探索这些 拥挤的多细胞生物膜背景下的细胞现象，我们也不知道如何 多细胞行为产生于这些单细胞特性。我实验室下一步的目标是 五年的时间将是了解单细胞的性质和当地环境的物理 在生物膜中产生有益的涌现行为。有了这个米拉奖，我的团队将 通过关注两个集体现象来探索这些问题：1)电细胞到细胞 交流和2)在生物膜过程中运动细胞和产生基质的细胞模式的出现 发展。我们将使用空间基因表达测量来解决这些问题， 生物膜的单细胞水平时间推移成像，以及用于电气的新型晶体管器件 生物膜的扰动。为了从单细胞属性探索群体行为的出现， 我们将使用实验生物膜模式物种枯草芽孢杆菌来扰乱已知的细胞间 通讯机制和基因调控电路。我们的数据将向量化 多细胞现象的模型，这将使我们从系统层面上理解 微生物中的多细胞行为，以及提出新的假设和目标 扰乱了让生物膜逃避治疗的紧急行为。

PROJECT SUMMARY Bacterial biofilms are communities of bacteria stuck together by a self-produced polymer matrix. They exist in nearly every environment on earth and are the cause of most hospital-borne infections. These adherent communities are highly tolerant of antibiotics and their extreme resilience cannot merely be attributed to the inability of drug molecules to penetrate the biofilm matrix. It has become clear that emergent, multicellular behaviors in biofilms impart unique survival strategies. In recent years, we have learned detailed mechanisms of gene regulation and phenotypic heterogeneity of single bacterial cells, but we have neither explored these cellular phenomena in the context of crowded, multicellular biofilms, nor do we understand how multicellular behaviors emerge from these single-cell properties. The goal of my lab for the next five years will be to understand how single-cell properties and physics of the local environment give rise to beneficial emergent behaviors in biofilms. With this MIRA award, my group will explore these questions by focusing on two collective phenomena: 1) electrical cell-to-cell communication and 2) emergence of patterns of motile and matrix-producing cells during biofilm development. We will approach these problems using spatial gene expression measurements, single-cell-level time-lapse imaging of biofilms, and novel transistor devices for electrical perturbation of biofilms. To probe the emergence of group behaviors from single-cell properties, we will use the experimental biofilm model species Bacillus subtilis to perturb known cell-to-cell communication mechanisms and gene regulatory circuits. Our data will inform quantitative models of multicellular phenomena, which will give us a system-level understanding of multicellular behaviors in microbes, as well as suggesting new hypotheses and targets for disrupting the emergent behaviors that allow biofilms to elude treatment.