Quorum sensing and lifestyle switching in Yersinia.

耶尔森氏菌是一种在人类和微生物学史上占有重要地位的细菌。鼠疫耶尔森氏菌是腺鼠疫和肺鼠疫的病原体，在周期性大流行中夺走了数百万人的生命，对人类历史的影响可能比任何其他细菌都要大。耶尔森氏菌还包括对动物（养殖和野生）、鸟类和鱼类具有致病性的种类。例如，假结核杆菌的生活方式在食物/水环境和哺乳动物胃肠道之间交替，感染牲畜以及圈养的动物园动物和鸟类。在人类中，它会导致胃肠道感染和涉及严重中毒性休克综合征的“远东猩红热”。鼠疫杆菌大约在2万年前从假结核杆菌进化而来，尽管这些病原体在基因水平上有98%相同，但它们引起的疾病却截然不同。然而，引起人类感染的耶尔森氏菌都具有相同的pYV染色体外质粒，这对毒力至关重要，因为它使耶尔森氏菌能够破坏宿主的免疫反应。作为单细胞微生物，yersinae能够适应各种环境压力（例如广泛波动的温度），从而促进在土壤和水环境中生存并从土壤和水环境迁移到不同的宿主（昆虫和动物）中。虽然细菌是单细胞的，但它们可以通过化学信号分子进行交流，并通过形成被称为生物膜的表面相关群落来协调它们的行为。在这里，细菌被包裹在一层“黏液”中，在极端环境下，这种黏液可以保护细菌免受免疫系统和抗生素的侵害。就耶尔森氏菌而言，黑死病是由跳蚤传播的，跳蚤的进食被消化道内稠密的鼠疫菌生物膜所阻断。鼠疫杆菌还通过在秀丽隐杆线虫的头部周围形成一层生物膜，阻止线虫的摄食。一些假结核杆菌菌株也很容易在秀丽隐杆线虫上形成生物膜，由于它作为病原体的危险性低于鼠疫杆菌，因此它提供了一种更安全、更简单的方法来研究活组织上的生物膜发育。这种生物膜模型也很有吸引力，因为很难在哺乳动物宿主中研究生物膜。秀丽隐杆线虫与人类共享许多基因，因此秀丽隐杆线虫/耶尔森菌模型可用于鉴定病原体和宿主的体内遗传特征，这些特征有助于生物膜介导的相互作用，这对耶尔森菌/跳蚤和人类以生物膜为中心的感染都具有有趣的意义。我们发现假结核杆菌使用一个复杂的双通道群体感应系统，根据当地普遍的环境条件做出生活方式决定，帮助生物体决定是建立一个生物膜，通过分泌Yop蛋白变得具有细胞毒性，还是游走并找到一个新的生态位来定居。该研究项目旨在在分子水平上深入了解假结核杆菌用于决定这些生活方式的信号级联，包括是否保留pYV毒力质粒。我们还将寻求进一步了解秀丽隐杆线虫宿主在生物膜形成过程中的作用：耶尔森菌附着的表面配体；以及生物膜发育过程中发生的信号传递过程。这项工作不仅将使我们了解致病细菌的基本生物学，而且从长远来看，可能有助于我们确定预防或治疗人类和其他动物疾病的新靶点。这对于经常引起慢性感染的生物膜尤其重要。这些都很难根除，因此研究生物膜是如何在活组织上形成的，可能会发现破坏和预防它们的新方法。

The Yersinia are bacteria which occupy a prominent place in the history of mankind and microbiology. Yersinia pestis, the causative agent of bubonic and pneumonic plague, has claimed millions of lives in periodic pandemics, influencing human history possibly to a greater extent than any other bacterium. The Yersiniae also include species which are pathogenic for animals (farmed and wild), birds and fish. For example, Y. pseudotuberculosis whose lifestyle alternates between the food/water environment and the mammalian gastrointestinal tract, infects livestock as well as captive zoo animals and birds. In humans it causes gastro-intestinal infections and 'far east scarlet-like' fever which involves a severe toxic shock syndrome. Y. pestis evolved from Y. pseudotuberculosis around 20,000 years ago and although these pathogens are >98% identical at the genetic level they cause very different diseases. However the Yersinia species which cause human infections all possess the same pYV extra-chromosomal plasmid which is essential for virulence since it enables Yersinia to subvert its host immune response. As unicellular micro-organisms, the Yersiniae are capable of adapting to diverse environmental stresses (e.g. widely fluctuating temperatures) that facilitate survival in, and migration from, soil and water environments into different hosts (both insects and animals). Although bacteria are single-celled, they can co-ordinate their behaviour by communicating via chemical signal molecules and by forming surface-associated communities known as biofilms. Here, bacteria become enmeshed in a 'slime' layer which confers protection in extreme environments and from the immune system and antibiotics. With respect to Yersinia, bubonic plague is transmitted by fleas whose feeding is blocked by a dense biofilm of Y. pestis in their digestive tracts. Y. pestis also blocks the feeding of the nematode worm, Caenorhabditis elegans, by forming a biofilm around its head. Some Y. pseudotuberculosis strains also readily form biofilms on C. elegans and because it is less dangerous as a pathogen than Y. pestis, it offers a much safer and simpler means of investigating biofilm development on living tissues. This biofilm model is also attractive because it is difficult to study biofilms in the mammalian host. C. elegans shares many genes with humans and so the C. elegans/Yersinia model can be used to identify in vivo genetic features of both the pathogen and the host that contribute to biofilm-mediated interactions which have interesting implications for both the Yersinia/flea and human biofilm-centred infections. We discovered that Y. pseudotuberculosis uses a sophisticated two channel quorum sensing system to make lifestyle decisions according to the prevailing local environmental conditions which help the organism decide whether to build a biofilm, become cytotoxic by secreting Yop proteins or swim away and find a new niche to colonize. This research project aims to gain insight, at the molecular level, into the signalling cascade used by Y. pseudotuberculosis to make these lifestyle decisions including whether to retain the pYV virulence plasmid. We will also seek to gain further insights into the role of the C. elegans host during biofilm formation: the surface ligands to which Yersinia attaches; and, the signalling processes occurring during development of the biofilm. This work will not only inform us about the basic biology of disease causing bacteria but in the longer term may help us to identify novel targets for the prevention or treatment of disease in humans and other animals. This is especially important with respect biofilms which are often the cause of chronic infections. These are very difficult to eradicate and therefore investigating how biofilms develop on living tissues may uncover novel ways for their disruption and prevention.