Grant: Operating Grant

Enteropathogenic E. coli (EPEC) are a leading cause of bacterial diarrhea, causing much morbidity and mortality in children worldwide. Enterohemorrhagic E. coli (EHEC; E. coli O157) is a close relative of EPEC which causes "hamburger disease" and hemolytic uremic syndrome (HUS), and was the source of the Walkerton, Ontario outbreak and a major spinach recall. EPEC and EHEC belong to a family of attaching and effacing pathogens that adhere to intestinal epithelial cells, causing a specialized disruption on the intestinal cell surface which mediates disease. This application addresses several fundamental questions pertaining to secreted pathogenic E. coli proteins that are virulence factors. This includes studying the structure and function of the type III secretion system needed to secrete and inject these effectors into host cells, including protein-protein interactions and regulation of secretion. New type III secreted factors will be identified and their contribution to disease studied in a relevant murine infection model. In addition, molecular characterization of the mammalian proteins that these factors interact with will be examined, as will their effects on host cells and in an animal disease model. Collectively, these studies will provide information about disease progression and the role of secreted virulence factors, which can be applied to design therapeutics and vaccines against diseases caused by these pathogens.