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Analysis of TcdB Proteins within the Hypervirulent Clade 2 Reveals an Impact of RhoA Glucosylation on Clostridium difficile Proinflammatory Activities
dc.creator | Quesada Gómez, Carlos | |
dc.creator | López Ureña, Diana | |
dc.creator | Chumbler, Nicole | |
dc.creator | Kroh, Heather K. | |
dc.creator | Castro Peña, Carolina | |
dc.creator | Rodríguez Sánchez, César | |
dc.creator | Orozco Aguilar, Josué | |
dc.creator | González Camacho, Sara María | |
dc.creator | Rucavado Romero, Alexandra | |
dc.creator | Guzmán Verri, Caterina | |
dc.creator | Lawley, Trevor D. | |
dc.creator | Lacy, D. Borden | |
dc.creator | Chaves Olarte, Esteban | |
dc.date.accessioned | 2017-07-12T17:07:59Z | |
dc.date.available | 2017-07-12T17:07:59Z | |
dc.date.issued | 2016-03 | |
dc.identifier.citation | http://iai.asm.org/content/84/3/856.full.pdf+html | |
dc.identifier.issn | 856-865 | |
dc.identifier.other | PMC4771349 | |
dc.identifier.uri | https://hdl.handle.net/10669/30354 | |
dc.description.abstract | 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. | es_ES |
dc.description.sponsorship | Wellcome Trust, United States a Trevor D Lawley bajo el número 098051 | es_ES |
dc.description.sponsorship | Consejo Nacional de Rectores/[803-B1-654]/CONARE/Costa Rica | es_ES |
dc.description.sponsorship | Consejo Nacional de Rectores/[803-B4-652]/CONARE/Costa Rica | es_ES |
dc.description.sponsorship | Universidad de Costa Rica/[803-B5-107]/UCR/Costa Rica | es_ES |
dc.description.sponsorship | Universidad de Costa Rica/[803-B5-108]/UCR/Costa Rica | es_ES |
dc.description.sponsorship | Consejo Nacional para Investigaciones Científicas y Tecnológicas/[FV-0004-13. HHS]/CONICIT/Costa Rica | es_ES |
dc.description.sponsorship | National Institutes of Health/[R01AI095755]/NIH/Estados Unidos | es_ES |
dc.language.iso | en_US | es_ES |
dc.rights | Atribución 3.0 Costa Rica | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/cr/ | * |
dc.source | Infection and Immunity; Volumen 84, Número 3, 856-865 | es_ES |
dc.subject | Clostridium difficile | es_ES |
dc.subject | NAP1V | es_ES |
dc.subject | Glucosyltransferase | es_ES |
dc.subject | Pathogen | es_ES |
dc.title | Analysis of TcdB Proteins within the Hypervirulent Clade 2 Reveals an Impact of RhoA Glucosylation on Clostridium difficile Proinflammatory Activities | es_ES |
dc.type | artículo original | |
dc.identifier.doi | 10.1128/IAI.01291-15 | |
dc.description.procedence | UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Enfermedades Tropicales (CIET) | es_ES |
dc.identifier.codproyecto | 803-B1-654 | |
dc.identifier.codproyecto | 803-B5-108 | |
dc.identifier.pmid | 26755157 |
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