Genomic analysis of regulatory networks for bacterial differentiation and multicellular behaviour

细菌是一种单细胞生物，通常被认为是独立生存和相互作用的。事实上，大多数细菌以大群体的形式存在；这种生活方式的一个主要优点是大大提高了对个体细胞的保护，使其免受环境压力的影响，如水分和营养的流失。群集是我们在大量细菌物种中观察到的少数主要类型的群落行为之一。在群集过程中，细菌排成一大群，一起在一个表面上迁移。这是一个医学上重要的现象：蜂群使细菌能够迅速传播到宿主有机体中否则无法到达的位置并引发感染。例如，变形杆菌是一种经常在医院引起危及生命的感染的细菌。这些细菌聚集在人造医疗植入物上，进入患者的泌尿道，并上升到肾脏。除了在医学上的重要性外，蜂群是研究生物学中两个基本过程的绝佳模型：(a)细胞如何变化，或“分化”成执行特定功能的不同细胞类型；(b)单细胞如何转变成协调其行为的多细胞群体。增加我们对这些过程的知识将有助于我们了解复杂的多细胞生物是如何存在的。细胞通过感知与表面的接触以及彼此之间的接触而开始蜂群。这引发了细胞的蜕变，细胞长度增加了20倍，并形成了长长的分子螺旋桨，称为鞭毛，从细胞表面向外延伸。这些细长的细胞（数以十亿计）排成一列，形成大型细菌筏，并在鞭毛同步旋转的推动下迁移。为了驱动这种转变，一系列复杂的分子信号将最初的刺激转化为激活或抑制群居所需的一组特定基因。我们知道其中许多基因的身份，比如那些负责鞭毛构造的基因。然而，同样清楚的是，还有数百人目前身份不明。此外，我们对传入的分子信号如何传递以控制这些基因的活性只有基本的了解。我们将通过建立我们和其他人之前在细菌遗传学、生物信息学和基因组学方面的工作来解决这些问题。通过利用现有方法和开发新技术，我们将确定参与细菌群集的全部基因，并揭示控制它们的机制。在此过程中，我们将揭示细胞分化和多细胞性的新原理，并发现防止细菌向感染部位移动的方法。

Bacteria are single-cell organisms typically viewed as living and acting independently of each other. In fact, most bacteria exist in large communities; a major advantage of this lifestyle is the greatly improved protection of individual cells from environmental stresses such as loss of water and nutrients. Swarming is one of the few main types of community behaviour that we observe across a large number of bacterial species. During swarming, bacteria align themselves in a large group and migrate together over a surface. This is a medically important phenomenon: swarming enables bacteria to travel rapidly to locations in the host organism that are otherwise inaccessible and initiate infections. For example, Proteus mirabilis is a bacterial species that frequently causes life-threatening infections acquired in hospitals. These bacteria swarm over and colonise artificial medical implants to enter the patients' urinary tract and ascend to the kidneys. In addition to its importance in medicine, swarming is an excellent model for studying two fundamental processes in biology: (a) how cells change, or 'differentiate' into distinct cell types that perform specific functions; and (b) how single cells transform into multicellular populations that coordinate their behaviour. Increasing our knowledge of these processes will help us understand how complex, multicellular organisms exist. Cells initiate swarming by sensing contact with a surface and with each other. This triggers a metamorphosis in which cells lengthen 20-fold and build long molecular propellers called flagella that extend outward from the cell surface. These elongated cells (that number in the billions) then align to form large bacterial rafts and migrate away propelled by synchronised flagella rotation. To drive the transition, a complex cascade of molecular signals convert the initial stimuli to activate or repress a specific set of genes required for swarming. We know the identity of many of these genes, such as those responsible for flagella construction. However, it is also clear that several hundred more are involved which are currently unidentified. Additionally, we only have a basic understanding of how incoming molecular signals are transmitted to control the activity of these genes. We will address these problems by building on our and others' previous work in bacterial genetics, bioinformatics and genomics. By using existing approaches and developing new techniques, we will identify the full complement of genes involved in bacterial swarming and uncover the mechanisms controlling them. In doing so, we will reveal new principles underlying cellular differentiation and multicellularity, as well as discover ways to prevent bacterial movement to infection sites.