;Structural studies into novel membrane associated virulence factors of Legionella pneumophila

细菌是生活在地球上广泛环境中的微小生物，包括人类和动物，它们对健康有积极和消极的影响。在这个应用程序中，我们提出了一些实验，这将有助于我们了解危险的细菌如何能够在环境中持续存在并导致人类疾病的某些方面。我们将专门研究嗜肺军团菌，这种细菌在水生系统（例如河流，水库，冷热水供应，冷却塔）中无处不在，在医院和酒店等大型建筑物中非常普遍。L.嗜肺菌引起军团病（一种经常致命的肺炎）和庞蒂亚克热（一种较温和的流感样疾病），并且在英国和全球，感染率每年都在增加。在环境L。嗜肺菌生活在生物膜中，与其他细菌聚集在一起，并被防御网覆盖。这可以保护它免受脱水等外部因素的影响，也可以免受其他生物和抗菌化合物的攻击。然而，单细胞生物变形虫仍然可以吃这些细菌和L。嗜肺菌已经发展出了生存的策略，通过进入它们内部并躲避攻击。一旦进入这些宿主，L.嗜肺军团菌生活在膜结合的隔室（含空泡的军团菌; LCV）中，在那里它逃避检测。不幸的是，某些类型的人类肺细胞与阿米巴原虫有相似之处，因此当人类接触受污染的水时，军团菌会引起疾病。L.嗜肺菌在细菌外分泌许多蛋白质，使其能够感知外部世界，与其他生物体相互作用，并操纵宿主阿米巴和人类细胞，以便它们能够在其中生存。例如，“II型分泌系统”（T2 SS）使用一种类似生物膜的机制来输出有助于形成生物膜的蛋白质，并使L。嗜肺菌完全致病我们已经确定了一类独特的蛋白质，一旦出口能够结合到表面的L。嗜肺军团菌，帮助它粘附在生物膜中的其他细菌上并识别宿主细胞;或者，当在宿主体内时，与含有军团菌的空泡结合，帮助它变得隐蔽，从而不被检测到。了解这些蛋白质的功能细节以及它们为什么定位于特定的细胞膜将对我们进一步了解L。嗜肺菌感染同样，这些研究也可能揭示其他细菌感染疾病的共同途径，这反过来可能有助于我们设计解除L。嗜肺菌和其他危险的病原体。

Bacteria are tiny organisms that live in a wide range of environments on the earth, including humans and animals, where they have both a positive and negative impact on health. In this application, we propose a number of experiments that will help us to understand certain aspects of how dangerous bacteria are able to persist in the environment and cause disease in humans. We will specifically study the bacterium Legionella pneumophila, which is ubiquitous in aquatic systems (e.g. rivers, reservoirs, hot/cold water supplies, cooling towers) and highly prevalent in large buildings such as hospitals and hotels. L. pneumophila causes Legionnaires' disease (an often-fatal pneumonia), and Pontiac fever, (a milder flu-like disease) and rates of infection are increasing each year, both in the UK and globally. Within the environment L. pneumophila lives within biofilms where it clumps together with other bacteria and is covered in a defensive mesh. This protects it from external factors such as dehydration but also from attack by other organisms and antibacterial compounds. However, single celled organisms called amoebae can still graze on these bacteria and L. pneumophila has developed strategies to survive by going inside them and hiding away from attack. Once inside these hosts, L. pneumophila lives within a membrane-bound compartment (the Legionella containing vacuole; LCV), where it evades detection. Unfortunately, some types of human lung cells share similarities with amoebae and therefore Legionella causes disease when humans come into contact with contaminated water. L. pneumophila secrete many proteins outside of the bacterium that allow it to sense the outside world, interact with other organisms and also manipulate host amoebae and human cells so that they can survive inside them. For example, the 'type II secretion system' (T2SS) uses a syringe-like mechanism to export proteins that help form biofilms and enables L. pneumophila to become fully virulent. We have identified a unique class of these proteins that once exported are able to either bind to the surface of L. pneumophila, helping it stick to other bacteria in biofilms and recognize host cells; or, when inside a host, bind to the Legionella containing vacuole, helping it to become camouflaged so that it is not detected. Understanding the details of how these proteins function and why they localize to their specific membranes will be crucial to further our knowledge of L. pneumophila infection. Likewise, these studies may also reveal common pathways for infectious disease used by other bacteria, which may in turn help us design compounds which disarm L. pneumophila and other dangerous pathogens.