| Sumario: |
Clostridium difficile induces antibiotic-associated di-arrhea through the production of toxin A and toxin B;the former toxin has been assumed to be responsible forthe symptoms of the disease. Several toxin A-negativestrains fromC. difficilehave recently been isolated fromclinical cases and have been reported to produce toxin Bvariants eliciting an atypical cytopathic effect. Ultra-structural analysis indicated these toxins induce arounding cytopathic effect and filopodia-like structures.Toxin B variants glucosylated R-Ras, and transfectionwith a constitutively active mutant of this GTPase pro-tected cells against their cytopathic effect. Treatment ofcells with toxin B variants induced detachment from theextracellular matrix and blockade of the epidermalgrowth factor-mediated phosphorylation of extracellu-lar-regulated protein kinases, demonstrating a deleteri-ous effect on the R-Ras-controlled avidity of integrins.Treatment with toxin B variants also induced a tran-sient activation of RhoA probably because of inactiva-tion of Rac1. Altogether, these data indicate that thecytopathic effect induced by toxin B variants is becauseof cell rounding and detachment mediated by R-Ras glu-cosylation, and the induction of filopodia-like struc-tures is mediated by RhoA activation. Implications forthe pathophysiology ofC. difficile-induced diarrhea arediscussed.
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