Defining the roles of TcdA and TcdB in localized gastrointestinal disease, systemic organ damage, and the host response during Clostridium difficile infections.

Glen P. Carter, Anjana Chakravorty, Tu Anh Pham Nguyen, Steven Mileto, Fernanda Schreiber, Lucy Li, Pauline Howarth, Simon Clare, Bliss Cunningham, Susan P. Sambol, Adam Cheknis, Iris Figueroa, Stuart Johnson, Dale Gerding, Julian I. Rood, Gordon Dougan, Trevor D. Lawley, Dena Lyras

mBio 6(3):e00551-15. 2 June 2015

Speaker: Yi-Ching Chiu (邱意晴)                    Time: 15:00~ 16:00, Sep.23, 2015

Commentator: Ching-Hao Teng (鄧景浩 教授)         Place: Room 601

Abstract:

  Clostridium difficile infection is the main cause of healthcare-associated diarrhea. During infection, C. difficile produces two exotoxins, toxin A (TcdA) and toxin B (TcdB), but their relative contributions to disease remain unclear. Experiments with purified toxins have indicated that TcdA alone is able to evoke the symptoms of C. difficile infection, but TcdB is unable to do so unless it is mixed with TcdA or there is prior damage to the gut mucosa. [1] However, another study indicated that TcdB is essential for C. difficile virulence and that a strain producing TcdA alone was avirulent. [2] This creates a paradox over the individual importance of TcdA and TcdB. The authors used three independent animal models to study the relative virulence of isogenic C. difficile toxin gene mutants. They found that TcdA⁺ TcdB^- mutants were attenuated in virulence in comparison to the wild-type (TcdA⁺ TcdB⁺) strain, while TcdA^- TcdB⁺ mutants were fully virulent. They also showed that infection with TcdB-producing strains causes severe gut and distal organ damage, like multiple organ dysfunction syndrome (MODS), a serious but poorly understood complication of CDI. [3] Overall, the authors showed that TcdB is the major virulence factor of C. difficile and provide new insights into the host response to C. difficile during infection. This work also provided novel discovery into the systemic host damage that can occur as a consequence of a localized gastrointestinal infection.

Reference:

1.       Lyerly, D. M., Saum, K. E., MacDonald, D. K. & Wilkins, T. D. 1985. Effects of Clostridium difficile toxins given intragastrically to animals. Infect. Immun. 47, 349–352

2.       Lyras, D. et al. 2009. Toxin B is essential for virulence of Clostridium difficile. Nature 458, 1176–1179

3.       Dobson G, Hickey C, Trinder J. 2003. Clostridium difficile colitis causing toxic megacolon, severe sepsis and multiple organ dysfunction syndrome. Intensive Care Med 29:1030.