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Infect. Immun. doi:10.1128/IAI.01690-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Enteropathogenic E. coli-induced Epidermal Growth Factor Receptor activation contributes to physiological alterations in intestinal epithelial cells

Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612

^* To whom correspondence should be addressed. Email: vish{at}uic.edu.

	Abstract

The diarrheagenic pathogen Enteropathogenic Escherichia coli (EPEC) is responsible for significant infant mortality and morbidity, particularly in developing countries. EPEC pathogenesis relies on a type III secretion system-mediated transfer of virulence effectors into host cells. EPEC modulates host cell survival and inflammation, although the proximal signaling pathways have not been well defined. We therefore examined the effect of EPEC on the epidermal growth factor receptor (EGFR), a known upstream activator of both the pro-survival phosphoinositide 3-kinase (PI3K)/Akt and pro-inflammatory MAP kinase pathways. EPEC induced the autophosphorylation of EGFR in intestinal epithelial cells within 15 minutes post-infection, with maximal phosphorylation being observed at 4 hours. Filter-sterilized supernatants of EPEC cultures also stimulated EGFR phosphorylation, suggesting that a secreted component(s) contributes to this activity. EPEC-induced EGFR phosphorylation was blocked by the pharmacological inhibitor tyrphostin AG1478, as well as by EGFR neutralizing antibodies. Inhibition of EGFR phosphorylation by AG1478 had no effect on bacterial adherence, actin recruitment to sites of attachment or EPEC-induced epithelial barrier function alteration. EPEC-mediated Akt phosphorylation, however, was inhibited both by AG1478 and EGFR neutralizing antibodies. Correspondingly, inhibition of EGFR activation increased the apoptosis/necrosis of infected epithelial cells. Inhibition of EGFR phosphorylation also curtailed EPEC-induced ERK1/2 (MAP kinase) phosphorylation and, correspondingly, the production of the pro-inflammatory cytokine interleukin 8 by infected epithelial cells. Our studies suggest that EGFR is a key proximal signaling molecule during EPEC pathogenesis.

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