Document Detail

Intrarectal instillation of Clostridium difficile toxin A triggers colonic inflammation and tissue damage: development of a novel and efficient mouse model of Clostridium difficile toxin exposure.
MedLine Citation:
PMID:  23045481     Owner:  NLM     Status:  MEDLINE    
Clostridium difficile, a major cause of hospital-acquired diarrhea, triggers disease through the release of two toxins, toxin A (TcdA) and toxin B (TcdB). These toxins disrupt the cytoskeleton of the intestinal epithelial cell, increasing intestinal permeability and triggering the release of inflammatory mediators resulting in intestinal injury and inflammation. The most prevalent animal model to study TcdA/TcdB-induced intestinal injury involves injecting toxin into the lumen of a surgically generated "ileal loop." This model is time-consuming and exhibits variability depending on the expertise of the surgeon. Furthermore, the target organ of C. difficile infection (CDI) in humans is the colon, not the ileum. In the current study, we describe a new model of CDI that involves intrarectal instillation of TcdA/TcdB into the mouse colon. The administration of TcdA/TcdB triggered colonic inflammation and neutrophil and macrophage infiltration as well as increased epithelial barrier permeability and intestinal epithelial cell death. The damage and inflammation triggered by TcdA/TcdB isolates from the VPI and 630 strains correlated with the concentration of TcdA and TcdB produced. TcdA/TcdB exposure increased the expression of a number of inflammatory mediators associated with human CDI, including interleukin-6 (IL-6), gamma interferon (IFN-γ), and IL-1β. Finally, we were able to demonstrate that TcdA was much more potent at inducing colonic injury than was TcdB but TcdB could act synergistically with TcdA to exacerbate injury. Taken together, our data indicate that the intrarectal murine model provides a robust and efficient system to examine the effects of TcdA/TcdB on the induction of inflammation and colonic tissue damage in the context of human CDI.
Simon A Hirota; Vadim Iablokov; Sarah E Tulk; L Patrick Schenck; Helen Becker; Jimmie Nguyen; Samir Al Bashir; Tanis C Dingle; Austin Laing; Jianrui Liu; Yan Li; Jeff Bolstad; George L Mulvey; Glen D Armstrong; Wallace K MacNaughton; Daniel A Muruve; Justin A MacDonald; Paul L Beck
Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-08
Journal Detail:
Title:  Infection and immunity     Volume:  80     ISSN:  1098-5522     ISO Abbreviation:  Infect. Immun.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-13     Completed Date:  2013-02-07     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  0246127     Medline TA:  Infect Immun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4474-84     Citation Subset:  IM    
Department of Medicine, University of Calgary, Calgary, Canada.
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MeSH Terms
Administration, Rectal
Bacterial Proteins / administration & dosage,  toxicity*
Bacterial Toxins / administration & dosage,  toxicity*
Clostridium difficile / metabolism,  pathogenicity*
Colon / pathology
Disease Models, Animal*
Dose-Response Relationship, Drug
Enterocolitis, Pseudomembranous / immunology,  mortality,  pathology*
Enterotoxins / administration & dosage,  toxicity*
Inflammation / immunology,  mortality,  pathology*
Mice, Inbred C57BL
Grant Support
ISO-106796//Canadian Institutes of Health Research; MOP-98004//Canadian Institutes of Health Research
Reg. No./Substance:
0/Bacterial Proteins; 0/Bacterial Toxins; 0/Enterotoxins; 0/tcdA protein, Clostridium difficile; 0/toxB protein, Clostridium difficile

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