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Nature. The role of toxin A and toxin B in Clostridium difficile infection
The role of toxin A and toxin B in Clostridium difficile infection (Nature, Letter, abstract, edited)
[Source: Nature, <cite cite="http://www.nature.com/nature/journal/v467/n7316/full/nature09397.html">Access : The role of toxin A and toxin B in Clostridium difficile infection : Nature</cite>. Abstract, edited.]
Nature 467, 711-713 (7 October 2010) | doi:10.1038/nature09397; Received 14 January 2010; Accepted 6 August 2010; Published online 15 September 2010
The role of toxin A and toxin B in Clostridium difficile infection
Sarah A. Kuehne 1,2, Stephen T. Cartman 1,2, John T. Heap 1, Michelle L. Kelly 1, Alan Cockayne 1 & Nigel P. Minton 1
1. Clostridia Research Group, Centre for Biomolecular Sciences, School of Molecular Medical Sciences, Nottingham Digestive Diseases Centre, NIHR Biomedical Research Unit, University of Nottingham, Nottingham NG7 2RD, UK
2. These authors contributed equally to this work.
Correspondence to: Nigel P. Minton 1 Email: nigel.minton@nottingham.ac.uk
Abstract
Clostridium difficile infection is the leading cause of healthcare-associated diarrhoea in Europe and North America1, 2. 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 mucosa3. However, a recent study indicated that toxin B is essential for C. difficile virulence and that a strain producing toxin A alone was avirulent4. 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 system5, 6 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.
1. Clostridia Research Group, Centre for Biomolecular Sciences, School of Molecular Medical Sciences, Nottingham Digestive Diseases Centre, NIHR Biomedical Research Unit, University of Nottingham, Nottingham NG7 2RD, UK
2. These authors contributed equally to this work.
Correspondence to: Nigel P. Minton1 Email: nigel.minton@nottingham.ac.uk
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------<cite cite="http://www.nature.com/nature/journal/v467/n7316/full/nature09397.html"></cite>
[Source: Nature, <cite cite="http://www.nature.com/nature/journal/v467/n7316/full/nature09397.html">Access : The role of toxin A and toxin B in Clostridium difficile infection : Nature</cite>. Abstract, edited.]
Nature 467, 711-713 (7 October 2010) | doi:10.1038/nature09397; Received 14 January 2010; Accepted 6 August 2010; Published online 15 September 2010
The role of toxin A and toxin B in Clostridium difficile infection
Sarah A. Kuehne 1,2, Stephen T. Cartman 1,2, John T. Heap 1, Michelle L. Kelly 1, Alan Cockayne 1 & Nigel P. Minton 1
1. Clostridia Research Group, Centre for Biomolecular Sciences, School of Molecular Medical Sciences, Nottingham Digestive Diseases Centre, NIHR Biomedical Research Unit, University of Nottingham, Nottingham NG7 2RD, UK
2. These authors contributed equally to this work.
Correspondence to: Nigel P. Minton 1 Email: nigel.minton@nottingham.ac.uk
Abstract
Clostridium difficile infection is the leading cause of healthcare-associated diarrhoea in Europe and North America1, 2. 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 mucosa3. However, a recent study indicated that toxin B is essential for C. difficile virulence and that a strain producing toxin A alone was avirulent4. 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 system5, 6 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.
1. Clostridia Research Group, Centre for Biomolecular Sciences, School of Molecular Medical Sciences, Nottingham Digestive Diseases Centre, NIHR Biomedical Research Unit, University of Nottingham, Nottingham NG7 2RD, UK
2. These authors contributed equally to this work.
Correspondence to: Nigel P. Minton1 Email: nigel.minton@nottingham.ac.uk
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------<cite cite="http://www.nature.com/nature/journal/v467/n7316/full/nature09397.html"></cite>