Dynamic regulation of epithelial cell survival by enteropathogenic E. coli

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Abstract Enteropathogenic E. coli (EPEC) is a diarrheagenic pathogen that is responsible for significant morbidity and mortality, especially amongst children below 5 years of age in developing countries. The precise mechanism by which EPEC causes diarrhea is presently not known. The bacteria elaborate a syringe-like type III secretion system which conveys key virulence factors directly into host intestinal epithelial cells. EPEC also produces other virulence factors including flagellin and bundle-forming pili. During the initial phase of infection, EPEC appears to specifically limit the death of the underlying epithelial cells. Our initial studies show that a type III secreted protein EspZ (EPEC secreted protein Z), as well as flagellin, activate host survival pathways and inhibit apoptosis. While flagellin-dependent host cell survival has recently been explored with other pathogens, the mechanism by which EspZ, a protein unique to EPEC and related bacteria, suppresses host cell death pathways is not known. We propose to further explore the contribution of EspZ and flagellin to host intestinal epithelial cell survival both in vitro and in vivo, and to dissect the mechanism by which EspZ mediates its protective functions. Premature death of host cells can be detrimental to colonization and, therefore, these proteins are likely critical for EPEC pathogenesis. Understanding their mechanisms of action could lead to future efforts to inhibit their function, and thereby control EPEC pathogenesis.