The Role of Toxin A and Toxin B in Clostridium Difficile Infection

Nature. 2010 Oct 7;467(7316):711-3. doi: 10.1038/nature09397. Epub 2010 Sep 15.

Abstract

Clostridium difficile infection is the leading cause of healthcare-associated diarrhoea in Europe and North America. During infection, C. difficile produces two key virulence determinants, toxin A and toxin B. Experiments with purified toxins have indicated that toxin A alone is able to evoke the symptoms of C. difficile infection, but toxin B is unable to do so unless it is mixed with toxin A or there is prior damage to the gut mucosa. However, a recent study indicated that toxin B is essential for C. difficile virulence and that a strain producing toxin A alone was avirulent. This creates a paradox over the individual importance of toxin A and toxin B. Here we show that isogenic mutants of C. difficile producing either toxin A or toxin B alone can cause fulminant disease in the hamster model of infection. By using a gene knockout system to inactivate the toxin genes permanently, we found that C. difficile producing either one or both toxins showed cytotoxic activity in vitro that translated directly into virulence in vivo. Furthermore, by constructing the first ever double-mutant strain of C. difficile, in which both toxin genes were inactivated, we were able to completely attenuate virulence. Our findings re-establish the importance of both toxin A and toxin B and highlight the need to continue to consider both toxins in the development of diagnostic tests and effective countermeasures against C. difficile.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing
  • Bacterial Toxins / antagonists & inhibitors
  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism*
  • Chlorocebus aethiops
  • Clostridium Infections / microbiology*
  • Clostridium difficile / classification
  • Clostridium difficile / genetics
  • Clostridium difficile / metabolism*
  • Clostridium difficile / pathogenicity*
  • Cricetinae
  • Disease Models, Animal
  • Enterotoxins / antagonists & inhibitors
  • Enterotoxins / genetics
  • Enterotoxins / metabolism*
  • Gene Deletion
  • HT29 Cells
  • Humans
  • Neutralization Tests
  • Vero Cells
  • Virulence / genetics

Substances

  • Antibodies, Neutralizing
  • Bacterial Toxins
  • Clostridium difficile lethal toxin B
  • Enterotoxins
  • tcdA protein, Clostridium difficile