Paper

Gap junction hemichannels contribute to the generation of diarrhea during infectious enteric disease

Julian Andrew Guttman^1,*, Ann En-Ju Lin², Yuling Li², John Bechberger², Christian C Naus², A Wayne Vogl², B Brett Finlay²

¹ Simon Fraser University, Canada;
² University of British Columbia, Canada

Correspondence to: Julian Andrew Guttman, Biological Sciences, Simon Fraser University, Room B8276, 8888 University Drive, Burnaby, V5A1S6, Canada; jguttman{at}sfu.ca

Accepted 27 August 2009

Objective: The attaching and effacing (A/E) pathogens enterohemorrhagic E. coli, enteropathogenic E. coli and C. rodentium colonize intestinal tracts, attach to enterocytes, collapse infected cell microvilli and alter numerous host cell processes during infection. Enterocyte alterations result in numerous small molecules being released from host cells that likely contribute to diarrheal phenotypes observed during these infections. One possible route for small molecules to be released from intestinal cells may be through functional gap junction hemichannels. Here we examine the involvement of these hemichannels during the diarrheal disease caused by A/E pathogens in vivo.

Design: Mice were infected with the diarrhea-causing murine A/E pathogen C. rodentium for 7 days. Connexin43 (Cx43) protein levels and immunolocalization in the colon were initially used to determine alterations during A/E bacterial infections in vivo. Connexin mimetic peptides and connexin permeable tracer molecules were used to gage the presence and function of unpaired connexin hemichannels. The role of Cx43 in diarrhea generation was assessed by comparing infections of wild-type mice to Cx43 mutant mice and determining the water abundance in the colonic luminal material.

Results: We demonstrate that Cx43 protein levels are increased in colonocytes during in vivo A/E bacterial infections, resulting in functionally open connexon hemichannels in apical membranes of infected cells. Moreover, infected Cx43 +/- mice do not suffer from diarrheal disease.

Conclusions: This study provides the first evidence that functional connexon hemichannels can occur in the intestine and are a novel molecular mechanism of water release during infectious diarrhea.

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