Analysis of TcdB Proteins within the Hypervirulent Clade 2 Reveals an Impact of RhoA Glucosylation on Clostridium difficile Proinflammatory Activities
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...
| Main Authors: | Quesada Gómez, Carlos, López Ureña, Diana, Chumbler, Nicole, Kroh, Heather K., Castro Peña, Carolina, Rodríguez Sánchez, César, Orozco Aguilar, Josué, González Camacho, Sara María, Rucavado Romero, Alexandra, Guzmán Verri, Caterina, Lawley, Trevor D., Lacy, D. Borden, Chaves Olarte, Esteban |
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| Format: | Artículo |
| Language: | Inglés |
| Published: |
2017
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| Subjects: | |
| Online Access: |
http://iai.asm.org/content/84/3/856.full.pdf+html https://hdl.handle.net/10669/30354 |
| Summary: |
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. |
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