Dynamic regulation of epithelial cell survival by enteropathogenic E. coli

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.