Toxin B is essential for virulence of Clostridium difficile

Dena Lyras, Jennifer Ruth O'Connor, Pauline M Howarth, Susan P Sambol, Glen Paul Carter, Tongted Phumoonna, Rachael Poon, Victoria Michelle Adams, Gayatri Vedantam, Stuart Johnson, Dale Gerding, Julian Ian Rood

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Abstract

Clostridium difficile is the leading cause of infectious diarrhoea in hospitals worldwide, because of its virulence, spore-forming ability and persistence1,2. C. difficile-associated diseases are induced by antibiotic treatment or disruption of the normal gastrointestinal flora3,4. Recently, morbidity and mortality resulting from C. difficileassociated diseases have increased significantly due to changes in the virulence of the causative strains and antibiotic usage patterns1,2,5,6. Since 2002, epidemic toxinotype III NAP1/027 strains1,2, which produce high levels of themajor virulence factors, toxinAand toxin B, have emerged. These toxins have 63 amino acid sequence similarity7 and are members of the large clostridial glucosylating toxin family, which are monoglucosyltransferases that are proinflammatory, cytotoxic and enterotoxic in the human colon8?10. Inside host cells, both toxins catalyse the transfer of glucose onto theRho family of GTPases, leading to cell death8,11.However, the role of these toxins in the context of a C. difficile infection is unknown. Here we describe the construction of isogenic tcdA and tcdB (encoding toxin A and B, respectively) mutants of a virulent C. difficile strain and their use in the hamster diseasemodel to show that toxin B is a key virulence determinant. Previous studies showed that purified toxin A alone can induce most of the pathology observed after infection of hamsterswith C. difficile8,9,12 and that toxin B is not toxic in animals unless it is co-administeredwith toxin A, suggesting that the toxins act synergistically12.Our work provides evidence that toxinB, not toxinA, is essential for virulence. Furthermore, it is clear that the importance of these toxins in the context of infection cannot be predicted exclusively from studies using purified toxins, reinforcing the importance of using the natural infection process to dissect the role of toxins in disease.
Original languageEnglish
Pages (from-to)1176 - 1179
Number of pages4
JournalNature
Volume458
Issue number7242
DOIs
Publication statusPublished - 2009

Cite this

Lyras, D., O'Connor, J. R., Howarth, P. M., Sambol, S. P., Carter, G. P., Phumoonna, T., Poon, R., Adams, V. M., Vedantam, G., Johnson, S., Gerding, D., & Rood, J. I. (2009). Toxin B is essential for virulence of Clostridium difficile. Nature, 458(7242), 1176 - 1179. https://doi.org/10.1038/nature07822