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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.
Diana López-Ureña; Josué Orozco-Aguilar; Yendry Chaves-Madrigal; Andrea Ramírez-Mata; Amanda Villalobos-Jimenez; Stefan Ost; Carlos Quesada-Gómez; César Rodríguez; Panagiotis Papatheodorou; Esteban Chaves-Olarte. 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 .
AMA StyleDiana López-Ureña, Josué Orozco-Aguilar, Yendry Chaves-Madrigal, Andrea Ramírez-Mata, Amanda Villalobos-Jimenez, Stefan Ost, Carlos Quesada-Gómez, César Rodríguez, Panagiotis Papatheodorou, Esteban Chaves-Olarte. 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.
Chicago/Turabian StyleDiana López-Ureña; Josué Orozco-Aguilar; Yendry Chaves-Madrigal; Andrea Ramírez-Mata; Amanda Villalobos-Jimenez; Stefan Ost; Carlos Quesada-Gómez; César Rodríguez; Panagiotis Papatheodorou; 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.
Clostridium difficile is a nosocomial agent affecting immunocompromised populations under antibiotic treatment. The clinical manifestations induced by this bacterium range from mild antibiotic-associated diarrhea to potentially fatal pseudomembranous colitis. Traditionally, all the signs and symptoms produced by C. difficile have been associated to the production of two toxins, toxin A and toxin B. Both toxins belong to the family of large clostridial cytotoxins (LCTs), and their mechanism of action relies on a series of complex steps. First, these toxins recognize cell-surface located receptors allowing the entrance in membrane-surrounded compartments. The toxins are then translocated through acid sensing-dependent conformational changes and the enzymatically active domain is released into the cytosol through an autoprocessing activity. This enzymatic domain modifies through glucosylation of small guanosine triphosphatase (GTPases) from the Rho and Ras families. Consequently, the signal transduction pathways mediated by these proteins are interrupted leading to the corresponding cytoskeletal alterations and different effects which might finally result in different types of cell death. In vivo, these toxins induce toxicity on epithelial cells lining the intestinal mucosa and induce a severe inflammatory reaction characterized by the recruitment of neutrophils and secretion of several cytokines. It is precisely a combination of dead intestinal epithelial cells combined with polymorphonuclear immune cells that constitutes the characteristic pseudomembrane observed in diarrheic depositions by patients suffering complications of this infection. In this chapter, the clinical manifestations induced by C. difficile toxins, the cellular consequences of their mechanism of action and the evolution of the pathogenicity locus where they are encoded are discussed in detail.
Diana López-Ureña; Carlos Quesada-Gómez; César Rodríguez; Esteban Chaves-Olarte. Role of Clostridium difficile Toxins in Antibiotic-Associated Diarrhea and Pseudomembranous Colitis. Toxins and Drug Discovery 2018, 153 -170.
AMA StyleDiana López-Ureña, Carlos Quesada-Gómez, César Rodríguez, Esteban Chaves-Olarte. Role of Clostridium difficile Toxins in Antibiotic-Associated Diarrhea and Pseudomembranous Colitis. Toxins and Drug Discovery. 2018; ():153-170.
Chicago/Turabian StyleDiana López-Ureña; Carlos Quesada-Gómez; César Rodríguez; Esteban Chaves-Olarte. 2018. "Role of Clostridium difficile Toxins in Antibiotic-Associated Diarrhea and Pseudomembranous Colitis." Toxins and Drug Discovery , no. : 153-170.
Clostridium difficile is a nosocomial agent affecting immunocompromised population under antibiotic treatment. The clinical manifestations induced by this bacterium range from mild antibiotic-associated diarrhea to potentially fatal pseudomembranous colitis. Traditionally, all the signs and symptoms produced by C. difficile have been associated to the production of two toxins, toxin A and toxin B. Both toxins belong to the family of large clostridial cytotoxins (LCTs), and their mechanism of action relies on a series of complex steps. First, these toxins recognize cell-surface located receptors allowing the entrance in membrane-surrounded compartments. The toxins are then translocated through acid sensing-dependent conformational changes and the enzymatically active domain is released into the cytosol through an autoprocessing activity. This enzymatic domain modifies through glucosylation small guanosine triphosphatase (GTPases) from the Rho and Ras families. Consequently, the signal transduction pathways mediated by these proteins are interrupted leading to the corresponding cytoskeletal alterations and different effects which might finally result in different types of cell death. In vivo, these toxins induce toxicity on epithelial cells lining the intestinal mucosa and induce a severe inflammatory reaction characterized by the recruitment of neutrophils and secretion of several cytokines. It is precisely a combination of dead intestinal epithelial cells combined with polymorphonuclear immune cells what constitutes the characteristic pseudomembrane observed in diarrheic depositions by patients suffering complications of this infection. In this chapter, the clinical manifestations induced by C. difficile toxins, the cellular consequences of their mechanism of action and the evolution of the pathogenicity locus where they are encoded are discussed in detail.
Diana López-Ureña; Carlos Quesada-Gómez; César Rodríguez; Esteban Chaves-Olarte. Role of Clostridium difficile Toxins in Antibiotic-Associated Diarrhea and Pseudomembranous Colitis. Toxins and Drug Discovery 2016, 1 -18.
AMA StyleDiana López-Ureña, Carlos Quesada-Gómez, César Rodríguez, Esteban Chaves-Olarte. Role of Clostridium difficile Toxins in Antibiotic-Associated Diarrhea and Pseudomembranous Colitis. Toxins and Drug Discovery. 2016; ():1-18.
Chicago/Turabian StyleDiana López-Ureña; Carlos Quesada-Gómez; César Rodríguez; Esteban Chaves-Olarte. 2016. "Role of Clostridium difficile Toxins in Antibiotic-Associated Diarrhea and Pseudomembranous Colitis." Toxins and Drug Discovery , no. : 1-18.
The epidemiology of Clostridium difficile infections is highly dynamic as new strains continue to emerge worldwide. Here we present a detailed analysis of a new C. difficile strain (ICC-45) recovered from a cancer patient in Brazil that died from severe diarrhea. A polyphasic approach assigned a new PCR-ribotype and PFGE macrorestriction pattern to strain ICC-45, which is toxigenic (tcdA(+), tcdB(+) and ctdB(+)) and classified as ST41 from MLST Clade 2 and toxinotype IXb. Strain ICC-45 encodes for a variant TcdB that induces a distinct CPE in agreement with its toxinotype. Unlike epidemic NAP1/027 strains, which are also classified to MLST Clade 2, strain ICC-45 is susceptible to fluoroquinolones and does not overproduce toxins TcdA and TcdB. However, supernatants from strain ICC-45 and a NAP1/027 strain produced similar expression of pro-inflammatory cytokines, epithelial damage, and oxidative stress response in the mouse ileal loop model. These results highlight inflammation and oxidative stress as common features in the pathogenesis of C. difficile Clade 2 strains. Finally, this work contributes to the description of differences in virulence among various C. difficile strains.
Cecília Leite Costa; Diana López-Ureña; Thiago De Oliveira Assis; Ronaldo A. Ribeiro; Rodrigo Otávio Silveira Silva; Maja Rupnik; Mark H. Wilcox; Alex Fiorini de Carvalho; Anderson Oliveira Do Carmo; Adriana Abalen Martins Dias; Cibele Barreto Mano de Carvalho; Esteban Chaves-Olarte; César Rodríguez; Carlos Quesada-Gómez; Gerly Anne De Castro Brito. A MLST Clade 2 Clostridium difficile strain with a variant TcdB induces severe inflammatory and oxidative response associated with mucosal disruption. Anaerobe 2016, 40, 76 -84.
AMA StyleCecília Leite Costa, Diana López-Ureña, Thiago De Oliveira Assis, Ronaldo A. Ribeiro, Rodrigo Otávio Silveira Silva, Maja Rupnik, Mark H. Wilcox, Alex Fiorini de Carvalho, Anderson Oliveira Do Carmo, Adriana Abalen Martins Dias, Cibele Barreto Mano de Carvalho, Esteban Chaves-Olarte, César Rodríguez, Carlos Quesada-Gómez, Gerly Anne De Castro Brito. A MLST Clade 2 Clostridium difficile strain with a variant TcdB induces severe inflammatory and oxidative response associated with mucosal disruption. Anaerobe. 2016; 40 ():76-84.
Chicago/Turabian StyleCecília Leite Costa; Diana López-Ureña; Thiago De Oliveira Assis; Ronaldo A. Ribeiro; Rodrigo Otávio Silveira Silva; Maja Rupnik; Mark H. Wilcox; Alex Fiorini de Carvalho; Anderson Oliveira Do Carmo; Adriana Abalen Martins Dias; Cibele Barreto Mano de Carvalho; Esteban Chaves-Olarte; César Rodríguez; Carlos Quesada-Gómez; Gerly Anne De Castro Brito. 2016. "A MLST Clade 2 Clostridium difficile strain with a variant TcdB induces severe inflammatory and oxidative response associated with mucosal disruption." Anaerobe 40, no. : 76-84.