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