Systemic Dissemination of Clostridium Difficile Toxins A and B Is Associated With Severe, Fatal Disease in Animal Models

J Infect Dis. 2012 Feb 1;205(3):384-91. doi: 10.1093/infdis/jir748. Epub 2011 Dec 5.

Abstract

Background: Clostridium difficile infection (CDI) can cause a wide range of disease, from mild diarrhea to fulminant systemic disease. The incidence of systemic CDI with fatal consequence has increased rapidly in recent years.

Methods: Using an ultrasensitive cytotoxicity assay, we measured C. difficile toxin A (TcdA) and C. difficile toxin B (TcdB) in sera and body fluids of piglets and mice exposed to C. difficile to investigate the relationship between the presence of toxins in body fluids and systemic manifestations of CDI.

Results: We found that both TcdA and TcdB disseminate systemically, with toxins present in the sera and body fluids of infected animals, and toxemia is significantly correlated with the development of systemic CDI. The systemic administration of neutralizing antibodies against both toxins blocked the development of systemic disease in mice. We measured cytokine concentrations in the sera of mice and piglets with systemic and nonsystemic CDI and found that proinflammatory mediators were considerably elevated in animals with systemic CDI.

Conclusion: Our study demonstrates the existence of a strong correlation between toxemia and the occurrence of systemic disease, supporting the hypothesis that systemic CDI is most likely due to the toxicity of TcdA and TcdB and the induction of proinflammatory cytokines by the toxins.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Neutralizing / administration & dosage
  • Antibodies, Neutralizing / immunology
  • Antitoxins / administration & dosage
  • Antitoxins / immunology
  • Bacterial Proteins / analysis
  • Bacterial Proteins / blood
  • Bacterial Proteins / toxicity*
  • Bacterial Toxins / analysis
  • Bacterial Toxins / blood
  • Bacterial Toxins / toxicity*
  • Body Fluids / chemistry
  • Cell Survival / drug effects
  • Clostridium Infections / complications
  • Clostridium Infections / mortality*
  • Clostridium difficile / pathogenicity*
  • Cytokines / blood
  • Cytological Techniques / methods
  • Disease Models, Animal
  • Enterotoxins / analysis
  • Enterotoxins / blood
  • Enterotoxins / toxicity*
  • Mice
  • Mice, Inbred C57BL
  • Swine
  • Toxemia / mortality*

Substances

  • Antibodies, Neutralizing
  • Antitoxins
  • Bacterial Proteins
  • Bacterial Toxins
  • Cytokines
  • Enterotoxins
  • tcdA protein, Clostridium difficile
  • toxB protein, Clostridium difficile