Deciphering the mechanism of action of Escherichia coli STb toxin using intestinal epithelial cells

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Enterotoxigenic Escherichia coli (ETEC) is responsible for major economic losses in animal production resulting from diarrhea. ETEC strains produce disease through attachment to host cells via colonization factors and then elaborate one or more type of enterotoxins that can act on the intestinal tissue. STb is one of the small molecular weight heat-stable toxins produced by ETEC. This virulence factor is now recognized as a major player in neonatal and post-weaning diarrhea in pigs. Although there have been many studies on STb, little comprehensive information is available on its mechanism of action compared to other enterotoxins produced by ETEC (such as LT and STa). It was shown that STb has to be internalized into a target cell to express toxicity. However, the internalization route of STb remains unknown. STb is classified as a cytotonic toxin; currently the accepted dogma to explain the secretion observed is that ion channels, in particular chloride, are stimulated together with an inhibition of sodium ions leading to an osmotic loss of water. Also, ion and water fluxes between epithelial cells are regulated by structures called tight junctions that seal the space between them. Preliminary data demonstrated that STb, as was shown also for other bacterial toxins, could act on TJs by opening these structures and permitting a loss of fluid. The goal of the research program is to study further the STb internalization pathway and TJ opening. We aim to decipher the mechanism of action of STb toxin. Fundamental understanding of the mechanism of action of this clinically important enterotoxin has potential for the development of preventive and/or therapeutic strategies to control STb-induced diarrheal disease.