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Infection and Immunity, September 2009, p. 3661-3669, Vol. 77, No. 9
0019-9567/09/$08.00+0 doi:10.1128/IAI.00558-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Antibiotic Treatment of Clostridium difficile Carrier Mice Triggers a Supershedder State, Spore-Mediated Transmission, and Severe Disease in Immunocompromised Hosts 
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Trevor D. Lawley,1*
Simon Clare,1
Alan W. Walker,2
David Goulding,1
Richard A. Stabler,3
Nicholas Croucher,2
Piero Mastroeni,4
Paul Scott,2
Claire Raisen,1
Lynda Mottram,1
Neil F. Fairweather,5
Brendan W. Wren,3
Julian Parkhill,2 and
Gordon Dougan1
Microbial Pathogenesis Laboratory,1 Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom,2 London School of Hygiene and Tropical Medicine, University of London, London, United Kingdom,3 Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom,4 Center for Molecular Microbiology and Infection, Imperial College of London, London, United Kingdom5
Received 19 May 2009/ Returned for modification 19 June 2009/ Accepted 23 June 2009
Clostridium difficile persists in hospitals by exploiting an infection cycle that is dependent on humans shedding highly resistant and infectious spores. Here we show that human virulent C. difficile can asymptomatically colonize the intestines of immunocompetent mice, establishing a carrier state that persists for many months. C. difficile carrier mice consistently shed low levels of spores but, surprisingly, do not transmit infection to cohabiting mice. However, antibiotic treatment of carriers triggers a highly contagious supershedder state, characterized by a dramatic reduction in the intestinal microbiota species diversity, C. difficile overgrowth, and excretion of high levels of spores. Stopping antibiotic treatment normally leads to recovery of the intestinal microbiota species diversity and suppresses C. difficile levels, although some mice persist in the supershedding state for extended periods. Spore-mediated transmission to immunocompetent mice treated with antibiotics results in self-limiting mucosal inflammation of the large intestine. In contrast, transmission to mice whose innate immune responses are compromised (Myd88–/–) leads to a severe intestinal disease that is often fatal. Thus, mice can be used to investigate distinct stages of the C. difficile infection cycle and can serve as a valuable surrogate for studying the spore-mediated transmission and interactions between C. difficile and the host and its microbiota, and the results obtained should guide infection control measures.
* Corresponding author. Mailing address: Microbial Pathogenesis Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom CB10 1SA. Phone: 01223 495 391. Fax: 01223 495 239. E-mail: tl2{at}sanger.ac.uk
Published ahead of print on 29 June 2009.
Supplemental material for this article may be found at http://iai.asm.org/.
Infection and Immunity, September 2009, p. 3661-3669, Vol. 77, No. 9
0019-9567/09/$08.00+0 doi:10.1128/IAI.00558-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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