Clostridium difficile Toxin B causes epithelial cell necrosis through an autoprocessing-independent mechanism.
PLoS Pathog
; 8(12): e1003072, 2012.
Article
em En
| MEDLINE
| ID: mdl-23236283
ABSTRACT
Clostridium difficile is the most common cause of antibiotic-associated nosocomial infection in the United States. C. difficile secretes two homologous toxins, TcdA and TcdB, which are responsible for the symptoms of C. difficile associated disease. The mechanism of toxin action includes an autoprocessing event where a cysteine protease domain (CPD) releases a glucosyltransferase domain (GTD) into the cytosol. The GTD acts to modify and inactivate Rho-family GTPases. The presumed importance of autoprocessing in toxicity, and the apparent specificity of the CPD active site make it, potentially, an attractive target for small molecule drug discovery. In the course of exploring this potential, we have discovered that both wild-type TcdB and TcdB mutants with impaired autoprocessing or glucosyltransferase activities are able to induce rapid, necrotic cell death in HeLa and Caco-2 epithelial cell lines. The concentrations required to induce this phenotype correlate with pathology in a porcine colonic explant model of epithelial damage. We conclude that autoprocessing and GTD release is not required for epithelial cell necrosis and that targeting the autoprocessing activity of TcdB for the development of novel therapeutics will not prevent the colonic tissue damage that occurs in C. difficile - associated disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Bactérias
/
Toxinas Bacterianas
/
Enterocolite Pseudomembranosa
/
Clostridioides difficile
/
Células Epiteliais
Tipo de estudo:
Etiology_studies
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
PLoS Pathog
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos