Ler a versatile global regulator from E. coli O157 and related strains

虽然通常情况下，大肠杆菌是一种“友好细菌”，但某些种类的大肠杆菌，尤其是O157大肠杆菌，可以引起人类严重的肠道感染，对幼儿和老年人构成特别的威胁。感染通常与食用牛肉和相关产品(特别是汉堡)有关，但也可能因食用受污染的蔬菜或参观农场而引起。为了在人类肠道中站稳脚跟，O157大肠杆菌使用一种复杂的分子注射器(称为III型分泌系统)将自己的蛋白质注入人类细胞。注射器的部署反过来又受到编码其组件的基因的控制。我们对一种名为LER的细菌蛋白质感兴趣，它调节这些III型分泌基因。尽管过去人们的兴趣只集中在LER如何调节III型分泌上，但我们有初步证据表明，LER调节细菌细胞的许多其他方面。我们现在希望证实和扩大这些发现，以获得全球全面了解LER在基因调控中的功能。我们还希望研究LER与其他蛋白质的相互作用，并检验我们的假设，即LER参与了一个感知蛋白质何时分泌并改变基因表达以响应这种分泌的系统。更好地了解LER如何调控大肠杆菌的毒力，将为开发和引入新的疫苗株铺平道路，不仅为预防和控制这种可怕的病原体，而且还可能预防和控制其他传染性微生物。在这项工作中，我们受益于(1)世界级的申请者团队(这三个申请者都在去年发表在《美国国家科学院院刊》等顶级期刊上)，(2)独特的研究环境，可以获得独特的关键技术和信息，以及(3)来自优秀合作者的投入，他们对我们试图在其他环境中解决的问题具有丰富的经验。

Already E. coli is generally a 'friendly bacterium', some kinds of E. coli, particularly E. coli O157, can cause severe gut infections in humans, posing a special threat to the very young and the very old. Infection is commonly associated with consumption of beef and related products (especially hamburgers), but can also result from consumption of contaminated vegetables or from farm visits. To gain a foothold in the human bowel, E. coli O157 uses a sophisticated molecular syringe (called a type III secretion system) to inject its own proteins into human cells. Deployment of the syringe is in turn controlled by regulation of the genes that encode its components. We are interested in a bacterial protein called Ler that regulates these type III secretion genes. Although interest in the past has focused exclusively on how Ler regulates type III secretion, we have preliminary evidence to suggest that Ler regulates many other facets of the bacterial cell. We now wish to confirm and expand on these findings to gain a global all-round view of Ler's function in gene regulation. We also wish to investigate Ler's interactions with other proteins and test our hypothesis that Ler is involved in a system for sensing when proteins are secreted and changing the expression of genes in response to such secretion. A better understanding of how Ler regulates virulence in E. coli will pave the way for the development and introduction of novel vaccine strains providing new approaches to the prevention and control not only of this fearsome pathogen, but also potentially of other infectious micro-organisms. In this work, we benefit from a (1) world-class team of applicants (all three have published in top journals such as Proceedings of the National Academy of Science in the last year), (2) an exceptional research environment with unique access to key technologies and information and (3) input from superb collaborators, who have broad experience of the kind of questions we are trying to address in other settings.