Quorum sensing and lifestyle switching in Yersinia.

耶尔森氏菌是在人类和微生物学历史上占有重要地位的细菌。鼠疫耶尔森菌是腺鼠疫和肺鼠疫的病原体，在周期性的大流行中夺去了数百万人的生命，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物种。例如，Y.假结核病，其生活方式在食物/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，它会引起胃肠道感染和“远东猩红热”，这涉及到严重的中毒性休克综合征。Y.鼠疫菌是从Y.这些病原体在大约2万年前就产生了假结核病，尽管这些病原体在基因水平上有98%以上的相同性，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属物种都具有相同的pYV染色体外质粒，这是毒力所必需的，因为它使耶尔森氏菌能够破坏其宿主免疫应答。作为单细胞微生物，耶尔森氏菌能够适应不同的环境压力（例如大幅波动的温度），这有助于在土壤和水环境中存活并从土壤和水环境迁移到不同的宿主（昆虫和动物）。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形成称为生物膜的表面相关群落来协调它们的行为。在这里，细菌陷入一个“粘液”层，在极端环境中提供保护，免受免疫系统和抗生素的侵害。关于耶尔森氏菌，腺鼠疫是由跳蚤传播的，跳蚤的进食被密集的耶尔森氏菌生物膜阻断。消化道里的鼠疫Y.鼠疫菌还通过在线虫头部周围形成生物膜来阻止线虫的进食。一些Y。假结核菌株也容易在C.因为它作为病原体比Y.鼠疫，它提供了一个更安全和更简单的手段，调查生物膜的发展活组织。这种生物膜模型也是有吸引力的，因为它是很难研究生物膜在哺乳动物宿主。C.秀丽隐杆线虫与人类有许多基因相同，因此C.线虫/耶尔森氏菌模型可用于鉴定病原体和宿主的体内遗传特征，这些遗传特征有助于生物膜介导的相互作用，这对耶尔森氏菌/跳蚤和人类生物膜中心的感染都具有有趣的意义。我们发现Y.假结核病使用复杂的双通道群体感应系统来根据主要的局部环境条件做出生活方式决定，这有助于生物体决定是否建立生物膜，通过分泌Yop蛋白质而变得具有细胞毒性，或者游走并找到新的生态位来定殖。本研究项目旨在从分子水平上深入了解Y。假结核病患者做出这些生活方式决定，包括是否保留pYV毒力质粒。我们还将寻求进一步深入了解C的作用。线虫在生物膜形成过程中的宿主：耶尔森氏菌附着的表面配体;以及生物膜发育过程中发生的信号传导过程。这项工作不仅可以让我们了解致病细菌的基本生物学，而且从长远来看，可以帮助我们确定预防或治疗人类和其他动物疾病的新靶点。这对于生物膜尤其重要，生物膜通常是慢性感染的原因。这些是很难根除的，因此研究生物膜如何在活组织上发展可能会发现新的方法来破坏和预防它们。

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.