title: Clostridium difficile Toxins TcdA and TcdB Cause Colonic Tissue Damage by Distinct Mechanisms.
abstract: 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.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Chumbler
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Farrow
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA The Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA Epithelial Biology Center, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Lapierre
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA The Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA Epithelial Biology Center, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Franklin
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA The Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA borden.lacy@vanderbilt.edu.
authors.forename: D Borden
authors.initials: DB
authors.lastname: Lacy
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001427:Bacterial Toxins / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016360:Clostridioides difficile / Q000472:pathogenicity*; D003106:Colon / Q000166:cytology*; D004768:Enterotoxins / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects*; D005964:Glucosyltransferases / Q000378:metabolism; D051379:Mice
chemical_list: D001427:Bacterial Toxins; D004768:Enterotoxins; D005964:Glucosyltransferases