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Toxins 2018, 10(9), 351; https://doi.org/10.3390/toxins10090351

Enterohemorrhagic E. coli (EHEC)—Secreted Serine Protease EspP Stimulates Electrogenic Ion Transport in Human Colonoid Monolayers

1
Department of Medicine, Division of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2
Department of Internal Medicine, Division of Gastroenterology & Hepatology, University of New Mexico, Albuquerque, NM 87131, USA
3
Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
4
Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 21 August 2018 / Revised: 23 August 2018 / Accepted: 29 August 2018 / Published: 1 September 2018
(This article belongs to the Section Bacterial Toxins)
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Abstract

One of the characteristic manifestations of Shiga-toxin-producing Escherichia coli (E. coli) infection in humans, including EHEC and Enteroaggregative E. coli O104:H4, is watery diarrhea. However, neither Shiga toxin nor numerous components of the type-3 secretion system have been found to independently elicit fluid secretion. We used the adult stem-cell-derived human colonoid monolayers (HCM) to test whether EHEC-secreted extracellular serine protease P (EspP), a member of the serine protease family broadly expressed by diarrheagenic E. coli can act as an enterotoxin. We applied the Ussing chamber/voltage clamp technique to determine whether EspP stimulates electrogenic ion transport indicated by a change in short-circuit current (Isc). EspP stimulates Isc in HCM. The EspP-stimulated Isc does not require protease activity, is not cystic fibrosis transmembrane conductance regulator (CFTR)-mediated, but is partially Ca2+-dependent. EspP neutralization with a specific antibody reduces its potency in stimulating Isc. Serine Protease A, secreted by Enteroaggregative E. coli, also stimulates Isc in HCM, but this current is CFTR-dependent. In conclusion, EspP stimulates colonic CFTR-independent active ion transport and may be involved in the pathophysiology of EHEC diarrhea. Serine protease toxins from E. coli pathogens appear to serve as enterotoxins, potentially significantly contributing to watery diarrhea. View Full-Text
Keywords: EHEC; serine protease EspP; human colonoid monolayers; SPATEs; diarrhea; short circuit current; CFTR; intracellular Ca2+ EHEC; serine protease EspP; human colonoid monolayers; SPATEs; diarrhea; short circuit current; CFTR; intracellular Ca2+
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Tse, C.M.; In, J.G.; Yin, J.; Donowitz, M.; Doucet, M.; Foulke-Abel, J.; Ruiz-Perez, F.; Nataro, J.P.; Zachos, N.C.; Kaper, J.B.; Kovbasnjuk, O. Enterohemorrhagic E. coli (EHEC)—Secreted Serine Protease EspP Stimulates Electrogenic Ion Transport in Human Colonoid Monolayers. Toxins 2018, 10, 351.

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