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J Infect Dis. 2017 Dec 27;217(1):147-157. doi: 10.1093/infdis/jix485.

In Colon Epithelia, Clostridium perfringens Enterotoxin Causes Focal Leaks by Targeting Claudins Which are Apically Accessible Due to Tight Junction Derangement.

Author information

1
Institute of Clinical Physiology, Charité-Universitätsmedizin Berlin, Germany.
2
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
3
Max-Delbrück-Center für Molekulare Medizin, Berlin, Germany.

Abstract

Clostridium perfringens enterotoxin (CPE) causes food poisoning and antibiotic-associated diarrhea. It uses some claudin tight junction proteins (eg, claudin-4) as receptors to form Ca2+-permeable pores in the membrane, damaging epithelial cells in small intestine and colon. We demonstrate that only a subpopulation of colonic enterocytes which are characterized by apical dislocation of claudins are CPE-susceptible. CPE-mediated damage was enhanced if paracellular barrier was impaired by Ca2+ depletion, proinflammatory cytokine tumor necrosis factor α, or dedifferentiation. Microscopy, Ca2+ monitoring, and electrophysiological data showed that CPE-mediated cytotoxicity and barrier disruption was limited by extent of CPE-binding. The latter was restricted by accessibility of non-junctional claudin molecules such as claudin-4 at apical membranes. Focal-leaks detected in HT-29/B6 colonic monolayers were verified for native tissue using colon biopsies. These mechanistic findings indicate how CPE-mediated effects may turn from self-limiting diarrhea into severe clinical manifestation such as colonic necrosis-if intestinal barrier dysfunction, eg, during inflammation facilitates claudin accessibility.

KEYWORDS:

Clostridium perfringens enterotoxin; HT-29/B6 cells; claudin; pore-forming toxin; tight junction

PMID:
28968861
DOI:
10.1093/infdis/jix485
[Indexed for MEDLINE]

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