Molecular Pathogenesis of Enterotoxigenic Escherichia coli Infections

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Enterotoxigenic Escherichia coli (ETEC) are an extraordinarily common cause of infectious diarrhea in resource limited areas of the planet where military personnel are frequently deployed. In endemic areas these pathogens are a major cause of morbidity as well as mortality in young children. The acute illness associated with these pathogens may range from mild diarrhea to severe, cholera-like disease associated with rapid dehydration. Travelers and military personnel deployed to endemic regions are highly susceptible to symptomatic illness caused by ETEC. Currently there is no vaccine to prevent these infections. In addition to the acute illness these pathogens are associated with a number of important but poorly understood sequelae including malabsorption and tropical enteropathy, growth stunting, and cognitive impairment in children as well as tropical malabsorption syndromes and irritable bowel syndrome in returning travelers. ETEC are defined by the production of enterotoxins that lead to net export of salt and water into the intestinal lumen. Most prior research effort has focused almost exclusively on the cellular effects of these toxins that lead to diarrhea. However, recent transcriptome studies of host cells following infection or treatment with toxin suggest that these enterotoxins may impart many collateral effects relevant to our understanding of key aspects of virulence associated with acute illness as well as the sequelae associated with these infections. The proposed studies will focus on the interaction of highly conserved E. coli fimbriae with a family of cell surface glycoproteins related to carcinoembryonic antigen (CEA), the carcinoembryonic antigen cell adhesion molecules (CEACAMs) that are expressed on intestinal epithelia. Interestingly our studies demonstrate that these molecules are strongly up-regulated by ETEC heat-labile toxin and that they may serve as a receptor for ETEC. Because these molecules play essential roles in cellular adhesion and maintenance of tissue architecture, modulation of their expression could play important roles in the sequelae associated with these infections.