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

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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.