Recognition by the type II secretion system and how it enables Legionella pneumophila to thrive

细菌是一种微小的有机体，存在于地球上的各种环境中。它们也可以生活在人类和动物体内，对健康既有积极的好处，也有消极的好处。在这项申请中，我提出了一些实验，以了解某些细菌如何导致疾病并在环境中持续存在的某些方面。具体地说，我将研究嗜肺军团菌，这是一种在天然和人造水环境中都很容易找到的细菌。这种细菌感染人类的肺部，导致军团病，一种通常致命的肺炎类型，以及庞蒂亚克热，一种较轻微的流感样疾病。在西方社会，储存和分配水的人造基础设施无处不在，因此在许多大型建筑(包括医院和酒店)中都发现了军团菌，军团病病例的数量正在增加。嗜肺性乳杆菌在环境中的高流行率是由于它在生物膜内生存的能力：被包裹在防护层中的复杂的多物种细菌团。这里的居民受到保护，不受环境、其他生物和抗菌化合物的影响。然而，水传播的阿米巴仍然可以捕食这些细菌，尽管嗜肺性乳杆菌已经开发出了一种策略，通过进入它们内部、躲避它们的检测和躲避任何攻击来生存。不幸的是，某些类型的哺乳动物肺细胞与各种阿米巴菌株有相似之处，这就是为什么军团菌是一种机会主义的病原体，当人类接触受污染的水时，它会导致疾病。军团菌使用“II型分泌系统”(T2SS)，这是一种类似注射器的机制，将蛋白质底物输送到环境中。这些底物促进生物被膜的形成，并使嗜肺乳杆菌成为完全毒力。他们也被证明对这种细菌广泛的宿主范围做出了贡献。例如，至少有18株阿米巴是嗜肺乳杆菌的自然宿主，为这种病原体创造了大量的环境宿主。然而，对于这些底物中的一些，我们并不确切地了解它们的靶标是什么，或者它们的具体作用是什么，尽管一些底物与疾病和嗜肺乳杆菌感染大范围阿米巴的能力有关。分析这些蛋白质中哪些对这些过程是重要的将是我将要研究的一个方面，但我的主要目标是研究嗜肺乳杆菌在这些底物分泌之前是如何识别它们的。了解这种T2SS如何部署这些底物的细节将为设计能够解除其武装的化合物提供基础。此外，这种类型的分泌系统对许多其他人类细菌病原体也是必不可少的，例如，向宿主排放毒素并导致疾病。因此，这些研究反过来也可能揭示出一种共同的新途径，在未来对抗其他类型的细菌感染。

Bacteria are tiny organisms that are present in a wide range of environments on the earth. They can also live within humans and animals where they have both positive and negative benefits to health. In this application I propose a number of experiments to understand certain aspects of how some bacteria cause disease and persist in the environment. Specifically I will be studying Legionella pneumophila, a bacterium that is readily found in both natural and man-made water environments. This bacterium infects the human lungs and causes Legionnaires' disease, an often-fatal type of pneumonia, and Pontiac fever, a milder flu-like disease. Man-made infrastructures that store and distribute water are ubiquitous in Western society and as such Legionella are found in many large buildings (including hospitals and hotels), with the number of Legionnaires' disease cases on the increase. The high prevalence of L. pneumophila within the environment is due to its ability to survive inside biofilms: complex multispecies bacterial masses encased in a defensive layer. Here the inhabitants are protected from the environment, other organisms and antibacterial compounds. However, water-borne amoebae can still graze on these bacteria, although L. pneumophila has developed strategies to survive by going inside them, evading their detection and hiding away from any attack. Unfortunately, some types of mammalian lung cells share similarities with various amoeba strains and this is why Legionella is an opportunistic pathogen that can cause disease when humans come into contact with contaminated water.Legionella use a 'type II secretion system' (T2SS), a syringe-like mechanism to transport protein substrates into their surroundings. These substrates promote the formation of biofilms and enable L. pneumophila to become fully virulent. They have also been shown to contribute to this bacterium's extensive host range. For example, at least 18 strains of amoeba are the natural hosts of L. pneumophila creating a substantial environmental reservoir of this pathogen. For some of these substrates, however, we do not understand exactly what they target or what their specific roles are, although several have been linked to disease and the ability of L. pneumophila to infect a broad range of amoebae. Analysing which of these proteins are important for these processes will be one aspect of what I shall be investigating but my main objective is to study how L. pneumophila recognizes these substrates before they are secreted. Understanding the details of how this T2SS deploys these substrates will provide the foundations to design compounds that can disarm it. Furthermore, this type of secretion system is also essential for many other human bacterial pathogens, to discharge toxins for example, into the host and cause disease. Therefore in turn, these studies may also reveal a common novel pathway to combat other types of bacterial infections in the future.