In Colon Epithelia, Clostridium perfringens Enterotoxin Causes Focal Leaks by Targeting Claudins Which are Apically Accessible Due to Tight Junction Derangement. (15th September 2017)

• Record Type: Journal Article
• Authors: Eichner, Miriam; Augustin, Christian; Fromm, Anja; Piontek, Anna; Walther, Wolfgang; Bücker, Roland; Fromm, Michael; Krause, Gerd; Schulzke, Jörg-Dieter; Günzel, Dorothee; Piontek, Jörg
• Is Part Of: Journal of infectious diseases. Volume 217:Number 1(2018)
• Page Start: 147
• Page End: 157
• Publication Date: 2017-09-15
• Subjects: claudin -- Clostridium perfringens enterotoxin -- HT-29/B6 cells -- pore-forming toxin -- tight junction; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jix485
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract : CPE targets a subpopulation of colonocytes, thereby inducing focal barrier leaks. CPE-mediated damage is restricted by an intact tight junctional barrier. Toxicity and barrier disruption by CPE are mediated by apically dislocated nonjunctional claudins that serve as CPE receptors. 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 Ca 2+ -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 Ca 2+ depletion, proinflammatory cytokine tumor necrosis factor α, or dedifferentiation. Microscopy, Ca 2+ 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.