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Article

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

by
C. Ming Tse
1,†,
Julie G. In
1,2,†,
Jianyi Yin
1,
Mark Donowitz
1,
Michele Doucet
1,
Jennifer Foulke-Abel
1,
Fernando Ruiz-Perez
3,
James P. Nataro
3,
Nicholas C. Zachos
1,
James B. Kaper
4 and
Olga Kovbasnjuk
1,2,*
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
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Toxins 2018, 10(9), 351; https://doi.org/10.3390/toxins10090351
Submission 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.
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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MDPI and ACS Style

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.; et al. Enterohemorrhagic E. coli (EHEC)—Secreted Serine Protease EspP Stimulates Electrogenic Ion Transport in Human Colonoid Monolayers. Toxins 2018, 10, 351. https://doi.org/10.3390/toxins10090351

AMA Style

Tse CM, In JG, Yin J, Donowitz M, Doucet M, Foulke-Abel J, Ruiz-Perez F, Nataro JP, Zachos NC, Kaper JB, et al. Enterohemorrhagic E. coli (EHEC)—Secreted Serine Protease EspP Stimulates Electrogenic Ion Transport in Human Colonoid Monolayers. Toxins. 2018; 10(9):351. https://doi.org/10.3390/toxins10090351

Chicago/Turabian Style

Tse, C. Ming, Julie G. In, Jianyi Yin, Mark Donowitz, Michele Doucet, Jennifer Foulke-Abel, Fernando Ruiz-Perez, James P. Nataro, Nicholas C. Zachos, James B. Kaper, and et al. 2018. "Enterohemorrhagic E. coli (EHEC)—Secreted Serine Protease EspP Stimulates Electrogenic Ion Transport in Human Colonoid Monolayers" Toxins 10, no. 9: 351. https://doi.org/10.3390/toxins10090351

APA Style

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. (2018). Enterohemorrhagic E. coli (EHEC)—Secreted Serine Protease EspP Stimulates Electrogenic Ion Transport in Human Colonoid Monolayers. Toxins, 10(9), 351. https://doi.org/10.3390/toxins10090351

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