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Article

Toxin B Variants from Clostridium difficile Strains VPI 10463 and NAP1/027 Share Similar Substrate Profile and Cellular Intoxication Kinetics but Use Different Host Cell Entry Factors

1
Facultad de Microbiología and Centro de Investigación en Enfermedades Tropicales, Universidad de Costa Rica, 10101 San José, Costa Rica
2
Facultad de Farmacia and Laboratorio de Ensayos Biológicos, Escuela de Medicina, Universidad de Costa Rica, 10101 San José, Costa Rica
3
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany
4
Institut für Pharmakologie und Toxikologie, Universitätsklinikum Ulm, D-89081 Ulm, Germany
*
Author to whom correspondence should be addressed.
Received: 8 May 2019 / Accepted: 14 May 2019 / Published: 17 June 2019
(This article belongs to the Special Issue Toxins Secretion and Translocation)
Clostridium difficile induces antibiotic-associated diarrhea due to the release of toxin A (TcdA) and toxin B (TcdB), the latter being its main virulence factor. The epidemic strain NAP1/027 has an increased virulence attributed to different factors. We compared cellular intoxication by TcdBNAP1 with that by the reference strain VPI 10463 (TcdBVPI). In a mouse ligated intestinal loop model, TcdBNAP1 induced higher neutrophil recruitment, cytokine release, and epithelial damage than TcdBVPI. Both toxins modified the same panel of small GTPases and exhibited similar in vitro autoprocessing kinetics. On the basis of sequence variations in the frizzled-binding domain (FBD), we reasoned that TcdBVPI and TcdBNAP1 might have different receptor specificities. To test this possibility, we used a TcdB from a NAP1 variant strain (TcdBNAP1v) unable to glucosylate RhoA but with the same receptor-binding domains as TcdBNAP1. Cells were preincubated with TcdBNAP1v to block cellular receptors, prior to intoxication with either TcdBVPI or TcdBNAP1. Preincubation with TcdBNAP1v blocked RhoA glucosylation by TcdBNAP1 but not by TcdBVPI, indicating that the toxins use different host factors for cell entry. This crucial difference might explain the increased biological activity of TcdBNAP1 in the intestine, representing a contributing factor for the increased virulence of the NAP1/027 strain. View Full-Text
Keywords: Clostridium difficile; NAP1/027 toxin B; receptor binding; frizzled receptors Clostridium difficile; NAP1/027 toxin B; receptor binding; frizzled receptors
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MDPI and ACS Style

López-Ureña, D.; Orozco-Aguilar, J.; Chaves-Madrigal, Y.; Ramírez-Mata, A.; Villalobos-Jimenez, A.; Ost, S.; Quesada-Gómez, C.; Rodríguez, C.; Papatheodorou, P.; Chaves-Olarte, E. Toxin B Variants from Clostridium difficile Strains VPI 10463 and NAP1/027 Share Similar Substrate Profile and Cellular Intoxication Kinetics but Use Different Host Cell Entry Factors. Toxins 2019, 11, 348. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11060348

AMA Style

López-Ureña D, Orozco-Aguilar J, Chaves-Madrigal Y, Ramírez-Mata A, Villalobos-Jimenez A, Ost S, Quesada-Gómez C, Rodríguez C, Papatheodorou P, Chaves-Olarte E. Toxin B Variants from Clostridium difficile Strains VPI 10463 and NAP1/027 Share Similar Substrate Profile and Cellular Intoxication Kinetics but Use Different Host Cell Entry Factors. Toxins. 2019; 11(6):348. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11060348

Chicago/Turabian Style

López-Ureña, Diana, Josué Orozco-Aguilar, Yendry Chaves-Madrigal, Andrea Ramírez-Mata, Amanda Villalobos-Jimenez, Stefan Ost, Carlos Quesada-Gómez, César Rodríguez, Panagiotis Papatheodorou, and Esteban Chaves-Olarte. 2019. "Toxin B Variants from Clostridium difficile Strains VPI 10463 and NAP1/027 Share Similar Substrate Profile and Cellular Intoxication Kinetics but Use Different Host Cell Entry Factors" Toxins 11, no. 6: 348. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11060348

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