Salmonella subversion of GTPase signalling at the host cell membrane, a key aspect of pathogen infection

细菌疾病对人类社会产生了巨大的影响，直到公共卫生革命和抗生素发现建立了健康的黄金时代。然而，它们继续在不发达国家和发达国家构成一个重大问题，造成广泛的痛苦、死亡和经济损失。随着我们改变环境，例如食物链的工业化，以及细菌对抗生素的抗药性越来越强，它们现在构成了一种不祥的威胁。臭名昭著的细菌病原体沙门氏菌在我们这样的国家导致食源性腹泻疾病，在发展中国家导致威胁生命的疾病，特别是在儿童和免疫系统薄弱的人中。在人类摄入沙门氏菌后，例如通过肉或蛋，沙门氏菌会强行进入宿主肠道的细胞，并引发宿主免疫反应，导致恶心、痉挛和腹泻。沙门氏菌能够在这种免疫反应中存活下来，并迅速繁殖，产生越来越强的疾病。为了启动宿主入侵，沙门氏菌向目标肠道细胞传递一组“效应器”蛋白质，这些蛋白质控制宿主细胞的细胞骨架和细胞形状。沙门氏菌使用几种方法来实现这一关键步骤。我们的实验室最近发现了一种机制，需要打开两个宿主细胞的分子开关，名为Arf1和rac1，使沙门氏菌内化。沙门氏菌指示其效应器Sope激活rac1，同时劫持类似的宿主蛋白Arno来激活Arf1。我们将应用细胞生物学和生化方法来准确调查Sope和Arno是如何合作的，沙门氏菌是如何控制这一过程的，以及其他重要的细菌病原体是否使用相同或相似的策略来引发疾病。我们将研究沙门氏菌进入细胞的其他途径，以及宿主免疫系统如何对这些细菌入侵者驱动的变化做出反应。获得的信息将为细菌如何利用宿主细胞提供新的见解，加强对我们自己细胞中关键过程的了解，并可能揭示新的病原体靶点来对抗感染。

Bacterial diseases have had an enormous influence on human society until revolutions in public health and antibiotic discovery established a golden era of health. They nevertheless continue to pose a major problem in both underdeveloped and developed countries, causing widespread suffering, death and economic damage. They now present an ominous threat as we change the environment e.g. industrialising the food chain, and as bacteria become more and more resistant to antibiotics.The infamous bacterial pathogen Salmonella causes food-borne diarrhoeal disease in countries like ours, and life-threatening illness in the developing world, especially among children and people with weakened immune systems. Following human ingestion, e.g. via meat or eggs, Salmonella forces its way into cells of the host intestine and provokes a host immune response which causes nausea, cramps, and diarrhoea. Salmonella is able to survive this immune response, and it multiplies rapidly, generating ever-stronger disease. To initiate host invasion Salmonella delivers into target intestinal cells a battery of 'effector' proteins, which hijack control of the host cell cytoskeleton and cell shape. Salmonella uses several ways to achieve this crucial step. Our laboratory has recently found a mechanism that requires two host cell 'molecular switches', named Arf1 and Rac1, to be turned on to cause Salmonella to be internalised. Salmonella directs its effector SopE to activate Rac1, while hijacking a comparable host protein, ARNO, to activate Arf1. We will apply cell biology and biochemical approaches to investigate precisely how SopE and ARNO cooperate, how Salmonella controls this process, and whether other important bacterial pathogens use the same or similar strategy to initiate disease. We will study the other pathways Salmonella uses to get inside cells, and how the host immune system responds to the changes driven by these bacterial intruders. The information gained will provide new insights into how bacteria exploit host cells, enhance understanding of key processes in our own cells, and may reveal new pathogen targets to combat infection.