Investigating the role of adherence in clostridium difficile pathogenesis
Date
2012
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Abstract
Clostridium difficile is an anaerobic, spore-forming bacterium and the etiologic agent of C. difficile infection. C. difficile has become the leading cause of antibioticassociated diarrhea in hospitalized patients and represents a significant burden to health care systems worldwide. The appearance, in the past decade, of hyper-virulent C. difficile has resulted in disease in traditionally low-risk populations and more severe disease outcomes. Two large toxins, Toxin A and Toxin B, are the main virulence factors of the organism, however, a growing body of evidence suggests that adherence and subsequent colonization may play an important role in C. difficile's pathogenic strategy. Although several putative adhesins have been described, their roles in the adherence process have yet to be uncovered. In the studies presented herein, a novel C. difficile adherence assay and a hamster model of infection are used to characterize two putative adhesins, FliC, the flagellin monomer, and FliD, the flagellar cap protein. An immunotherapeutic approach revealed that FliD and not FliC-specific IgY antibodies prevented adherence to intestinal tissue culture cells and disease in hamsters. Gene knock-outs injliC andjliD showed that neither protein was essential for adherence and that both strains were still pathogenic in hamsters. These results imply that motility is not necessary for the organism to reach or colonize the site of infection and that down-regulation of flagellar proteins may be part of C. difficile's pathogenic strategy to avoid recognition by the host immune system. It is apparent that while FliC and FliD are not essential to the virulence of the organism, antibodies directed against FliD can still prevent disease, perhaps by aggregation and subsequent elimination of the organism from the host. Finally, an as yet reported function for Toxin B in facilitating adherence of the organism to intestinal tissue culture cells in vitro is described. Based on the combined results from the described studies, an updated model of the C. difficile adherence process is suggested. Current work is aimed at characterizing other putative adhesins by ClosTron mutagenesis, establishing a mouse model of infection and further developing the FliD-specific IgY immunotherapy in Phase II clinical trials.
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Bibliography: p. 158-185
A few page are in colour.
Includes copies of ethics approval and animal protocol approvals. Original copies with original Partial Copyright Licence.
A few page are in colour.
Includes copies of ethics approval and animal protocol approvals. Original copies with original Partial Copyright Licence.
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Citation
Dingle, T. C. (2012). Investigating the role of adherence in clostridium difficile pathogenesis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/4897