Clostridium difficile Toxins TcdA and TcdB Cause Colonic Tissue Damage by Distinct Mechanisms.

Chumbler NM, Farrow MA, Lapierre LA, Franklin JL, Lacy DB
Infect Immun. 2016 84 (10): 2871-7

PMID: 27456833 · PMCID: PMC5038081 · DOI:10.1128/IAI.00583-16

As the major cause of antibiotic-associated diarrhea, Clostridium difficile is a serious problem in health care facilities worldwide. C. difficile produces two large toxins, TcdA and TcdB, which are the primary virulence factors in disease. The respective functions of these toxins have been difficult to discern, in part because the cytotoxicity profiles for these toxins differ with concentration and cell type. The goal of this study was to develop a cell culture model that would allow a side-by-side mechanistic comparison of the toxins. Conditionally immortalized, young adult mouse colonic (YAMC) epithelial cells demonstrate an exquisite sensitivity to both toxins with phenotypes that agree with observations in tissue explants. TcdA intoxication results in an apoptotic cell death that is dependent on the glucosyltransferase activity of the toxin. In contrast, TcdB has a bimodal mechanism; it induces apoptosis in a glucosyltransferase-dependent manner at lower concentrations and glucosyltransferase-independent necrotic death at higher concentrations. The direct comparison of the responses to TcdA and TcdB in cells and colonic explants provides the opportunity to unify a large body of observations made by many independent investigators.

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

MeSH Terms (12)

Analysis of Variance Animals Apoptosis Bacterial Toxins Cell Death Cells, Cultured Clostridioides difficile Colon Enterotoxins Epithelial Cells Glucosyltransferases Mice

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