期刊
JOURNAL OF INFECTIOUS DISEASES
卷 217, 期 1, 页码 147-157出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jix485
关键词
claudin; Clostridium perfringens enterotoxin; HT-29/B6 cells; pore-forming toxin; tight junction
资金
- Sonnenfeld-Stiftung
- Deutsche Forschungsgemeinschaft (DFG) [Schu 559/11-3, FOR 721/2]
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 a, 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.
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