Subversion of actin cytoskeleton dynamics by the WxxxE effector proteins Map, EspM2 and EspS

大肠杆菌生活在人的肠道中，通常是无害的。然而，几种大肠杆菌菌株已经获得了额外的基因，使它们能够造成损害并导致疾病。致病性大肠杆菌是全世界腹泻疾病的最重要细菌原因之一，每年导致发展中国家数十万婴儿和幼儿死亡，其中一个例子是致病性大肠杆菌(EPEC)。与EPEC一样，其他腹泻病原体，包括肠出血性大肠杆菌(EHEC)、沙门氏菌和志贺氏菌，也是导致发展中国家儿童发病率和死亡率的重要肠道病原体。这些病原体也是旅行者的常见原因吗？腹泻。此外，EHEC感染可导致出血性结肠炎和溶血性尿毒症综合征(HUS)；EHEC诱导的HUS现在是英国和美国急性儿科肾功能衰竭的主要原因。伤寒沙门氏菌是伤寒的病原体。在发展中国家和发达国家，这些疾病造成的经济负担都是巨大的。我们现在知道，当这些细菌直接将被称为效应器的毒力蛋白注入肠道细胞时，疾病就会引起。因此，了解这些不同的效应器在细胞内的作用对于了解它们如何导致疾病至关重要。根据一个共同的和关键的基序，这些病原体表达的一些效应蛋白最近被归类为一类(被称为WxxxE效应蛋白)。在这项研究中，我们将重点关注三个WxxxE蛋白的例子，并利用体外(生物化学和细胞培养方法)和体内模型研究它们的功能和在疾病中的作用。这项研究无疑将揭示WxxxE蛋白的功能和细菌定植机制的新见解。更好地了解这些效应器对于开发有效的治疗方法至关重要，并将增强我们对病原菌如何为自身利益劫持细胞功能的一般理解。

Escherichia coli bacteria live in the human gut and are normally harmless. However, several strains of E. coli have acquired additional genes that enable them to inflict damage and cause disease. One example of such pathogenic E. coli, which is among the most important bacterial causes of diarrhoeal disease worldwide and responsible for deaths of hundreds of thousands of babies and young infants in developing countries each year, is enteropathogenic E. coli (EPEC). Like EPEC, other diarrhoeal pathogens, including enterohaemorrhagic E. coli (EHEC), Salmonella and Shigellea are also important enteric pathogens responsible for child morbidity and mortality in developing countries. These pathogens are also common causes of travellers? diarrhoea. Moreover, EHEC infection can lead to haemorrhagic colitis and haemolytic uraemic syndrome (HUS); EHEC-induced HUS is now the leading cause of acute paediatric renal failure in the UK and US. Salmonella typhi is the causative agent of typhoid fever. In both developing and developed countries the economical burden of these diseases is vast. We now know that disease is caused when these bacteria directly inject virulence proteins, known as effectors, into gut cells. Therefore, understanding what these different effectors do inside the cell is crucial to understanding how they cause disease. Based on a common and a critical motif, a number of effector proteins expressed by these pathogens were recently grouped into one category (refer to as the WxxxE effectors). In this study we will focus on three example WxxxE proteins and study their function and role in disease using in vitro (biochemistry and cell culture methodologies) and in vivo models. The study will undoubtedly reveal new insights into the function of WxxxE proteins and mechanisms of bacterial colonisation. Better understanding of these effectors is essential for development of effective treatments and will enhance our general understanding of how pathogenic bacteria hijack cell functions for their own advantage.