Salmonella effectors that modulate host responses to infection

沙门氏菌是引起肠胃炎和伤寒等多种人类疾病的重要细菌病原体。沙门氏菌可以入侵并在宿主细胞内生长，包括专门的白细胞（巨噬细胞），其功能是摧毁潜在的病原体。在进入宿主细胞后，沙门氏菌居住在膜囊（液泡）内，并通过它转移大量毒力蛋白，其中一些被插入液泡膜本身。这些细菌蛋白质有几种不同的功能：其中一些使细菌能够在液泡内生长，最近的证据表明，其他蛋白质阻断宿主细胞向其他细胞发送警报信号以发动免疫反应的能力。第三组蛋白质在细菌在细胞内复制后导致被感染细胞死亡。我们已经确定了一些涉及的蛋白质，并对它们的工作原理有了一些了解。拟议的研究包括在分子水平上对其功能的详细调查，包括细胞靶标的鉴定。它们必须与宿主相互作用才能干扰宿主。在此过程中，我们可能会发现病原体和宿主细胞生物学的新过程，这可能会对其他重要的细胞内病原体产生影响。我们的工作还可能为设计合理设计的新型疫苗提供有价值的信息，这些疫苗对于提供有效的长期保护以抵御沙门氏菌和其他细菌病原体至关重要。通过广播采访、报纸和杂志文章，以及帝国理工学院和发表我们工作的科学期刊的新闻稿，我们的工作信息已经传达给了非专业公众。例如，我曾接受过《今日节目》（BBC Radio 4）的采访，《每日电讯报》和《金融时报》也曾刊登过关于我们工作的文章。

Salmonella species are important bacterial pathogens causing a variety of human diseases, such as gastroenteritis and typhoid. Salmonella can invade and grow inside the cells of its host, including specialised white blood cells (macrophages) whose function is to destroy potential pathogens. Having entered host cells, Salmonella resides within a membranous sac (vacuole), and transfers through it a large number of virulence proteins, some of which are inserted into the vacuole membrane itself. These bacterial proteins have several different functions: some of them enable bacteria to grow inside the vacuole, and recent evidence indicates that others block the ability of host cells to send alarm signals to other cells to mount an immune response. A third set of proteins causes the infected cells to die after bacteria have replicated within them. We have identified some of the proteins involved and have gained some insights as to how they work. The proposed research involves detailed investigations into their functions at the molecular level, including the identification of the cellular ?targets? with which they must interact to interfere with the host. In the process we are likely to discover new processes of pathogen and host cell biology, which could have implications for other important intracellular pathogens. Our work is also likely to provide valuable information for the design of novel, rationally designed vaccines, which are essential to provide effective long term protection against Salmonella and other bacterial pathogens.Information about our work has been communicated to the lay public through radio interviews and newspaper and magazine articles, following press releases from Imperial College and the scientific journals which publish our work. For example, I have been interviewed on the Today Programme (BBC Radio 4), and articles on our work have appeared in the Daily Telegraph and The Financial Times.