title: Systemic dissemination of Clostridium difficile toxins A and B is associated with severe, fatal disease in animal models.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Tufts Cummings School of Veterinary Medicine, North Grafton, Massachusetts, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Steele
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.forename: Xingmin
authors.initials: X
authors.lastname: Sun
authors.forename: Yongrong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Haiying
authors.initials: H
authors.lastname: Wang
authors.forename: Saul
authors.initials: S
authors.lastname: Tzipori
authors.forename: Hanping
authors.initials: H
authors.lastname: Feng
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000276:immunology; D000992:Antitoxins / Q000008:administration & dosage / Q000276:immunology; D001426:Bacterial Proteins / Q000032:analysis / Q000097:blood / Q000633:toxicity*; D001427:Bacterial Toxins / Q000032:analysis / Q000097:blood / Q000633:toxicity*; D001826:Body Fluids / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D016360:Clostridioides difficile / Q000472:pathogenicity*; D003015:Clostridium Infections / Q000150:complications / Q000401:mortality*; D016207:Cytokines / Q000097:blood; D003584:Cytological Techniques / Q000379:methods; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000032:analysis / Q000097:blood / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D013552:Swine; D014115:Toxemia / Q000401:mortality*
chemical_list: D057134:Antibodies, Neutralizing; D000992:Antitoxins; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D016207:Cytokines; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile