Analysis of TcdB proteins within the hypervirulent clade 2 reveals an impact of RhoA glucosylation on Clostridium difficile proinflammatory activities
Enregistré dans:
Auteurs: | , , , , , , , , , , , , |
---|---|
Format: | artículo |
Date de publication: | 2016 |
Description: | Clostridium difficile strains within the hypervirulent clade 2 are responsible for nosocomial outbreaks worldwide. The increased pathogenic potential of these strains has been attributed to several factors but is still poorly understood. During a C. difficile outbreak, a strain from this clade was found to induce a variant cytopathic effect (CPE), different from the canonical arborizing CPE. This strain (NAP1V) belongs to the NAP1 genotype but to a ribotype different from the epidemic NAP1/RT027 strain. NAP1V and NAP1 share some properties, including the overproduction of toxins, the binary toxin, and mutations in tcdC. NAP1V is not resistant to fluoroquinolones, however. A comparative analysis of TcdB proteins from NAP1/RT027 and NAP1V strains indicated that both target Rac, Cdc42, Rap, and R-Ras but only the former glucosylates RhoA. Thus, TcdB from hypervirulent clade 2 strains possesses an extended substrate profile, and RhoA is crucial for the type of CPE induced. Sequence comparison and structural modeling revealed that TcdBNAP1 and TcdBNAP1V share the receptor-binding and autoprocessing activities but vary in the glucosyltransferase domain, consistent with the different substrate profile. Whereas the two toxins displayed identical cytotoxic potencies, TcdBNAP1 induced a stronger proinflammatory response than TcdBNAP1V as determined in ex vivo experiments and animal models. Since immune activation at the level of intestinal mucosa is a hallmark of C. difficile-induced infections, we propose that the panel of substrates targeted by TcdB is a determining factor in the pathogenesis of this pathogen and in the differential virulence potential seen among C. difficile strains. |
Pays: | Repositorio UNA |
Institution: | Universidad Nacional de Costa Rica |
Repositorio: | Repositorio UNA |
Langue: | Inglés |
OAI Identifier: | oai:https://repositorio.una.ac.cr:11056/17573 |
Accès en ligne: | http://hdl.handle.net/11056/17573 |
Access Level: | acceso abierto |
Mots-clés: | CLOSTRIDIUM DIFFICILE PROTEÍNAS PROTEINS TcdB |