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Open AccessArticle

Clostridium perfringens Epsilon-Toxin Impairs the Barrier Function in MDCK Cell Monolayers in a Ca2+-Dependent Manner

1
Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
2
Laboratory of Molecular Microbiological Science, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan
3
Faculty of Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama-shi, Kanagawa 245-0066, Japan
*
Author to whom correspondence should be addressed.
Toxins 2020, 12(5), 286; https://doi.org/10.3390/toxins12050286
Received: 27 March 2020 / Revised: 21 April 2020 / Accepted: 28 April 2020 / Published: 30 April 2020
(This article belongs to the Section Bacterial Toxins)
Epsilon-toxin produced by Clostridium perfringens significantly contributes to the pathogeneses of enterotoxemia in ruminants and multiple sclerosis in humans. Epsilon-toxin forms a heptameric oligomer in the host cell membrane, promoting cell disruption. Here, we investigate the effect of epsilon-toxin on epithelial barrier functions. Epsilon-toxin impairs the barrier integrity of Madin-Darby Canine Kidney (MDCK) cells, as demonstrated by decreased transepithelial electrical resistance (TEER), increased paracellular flux marker permeability, and the decreased cellular localization of junctional proteins, such as occludin, ZO-1, and claudin-1. U73122, an endogenous phospholipase C (PLC) inhibitor, inhibited the decrease in TEER and the increase in the permeability of flux marker induced by epsilon-toxin. The application of epsilon-toxin to MDCK cells resulted in the biphasic formation of 1,2-diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3). U73122 blocked the formation of DAG and IP3 induced by the toxin. Epsilon-toxin also specifically activated endogenous PLC-γ1. Epsilon-toxin dose-dependently increased the cytosolic calcium ion concentration ([Ca2+]i). The toxin-induced elevation of [Ca2+]i was inhibited by U73122. Cofilin is a key regulator of actin cytoskeleton turnover and tight-junction (TJ) permeability regulation. Epsilon-toxin caused cofilin dephosphorylation. These results demonstrate that epsilon-toxin induces Ca2+ influx through activating the phosphorylation of PLC-γ1 and then causes TJ opening accompanied by cofilin dephosphorylation. View Full-Text
Keywords: C. perfringens epsilon-toxin; barrier integrity; oligomer formation; cofilin; Ca2+ influx C. perfringens epsilon-toxin; barrier integrity; oligomer formation; cofilin; Ca2+ influx
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MDPI and ACS Style

Nagahama, M.; Seike, S.; Ochi, S.; Kobayashi, K.; Takehara, M. Clostridium perfringens Epsilon-Toxin Impairs the Barrier Function in MDCK Cell Monolayers in a Ca2+-Dependent Manner. Toxins 2020, 12, 286. https://doi.org/10.3390/toxins12050286

AMA Style

Nagahama M, Seike S, Ochi S, Kobayashi K, Takehara M. Clostridium perfringens Epsilon-Toxin Impairs the Barrier Function in MDCK Cell Monolayers in a Ca2+-Dependent Manner. Toxins. 2020; 12(5):286. https://doi.org/10.3390/toxins12050286

Chicago/Turabian Style

Nagahama, Masahiro; Seike, Soshi; Ochi, Sadayuki; Kobayashi, Keiko; Takehara, Masaya. 2020. "Clostridium perfringens Epsilon-Toxin Impairs the Barrier Function in MDCK Cell Monolayers in a Ca2+-Dependent Manner" Toxins 12, no. 5: 286. https://doi.org/10.3390/toxins12050286

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