Antibiotic treatment of Clostridium difficile carrier mice triggers a supershedder state, spore-mediated transmission, and severe disease in immunocompromised hosts

Trevor D Lawley, Simon Clare, Alan W Walker, David Goulding, Richard A Stabler, Nicholas Croucher, Piero Mastroeni, Paul Scott, Claire Raisen, Lynda Mottram, Neil F Fairweather, Brendan W Wren, Julian Parkhill, Gordon Dougan

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Abstract

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.
Original languageEnglish
Pages (from-to)3661-3669
Number of pages9
JournalInfection and Immunity
Volume77
Issue number9
Early online date29 Jun 2009
DOIs
Publication statusPublished - Sep 2009

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Keywords

  • animals
  • anti-bacterial agents
  • carrier state
  • Clostridium difficile
  • enterocolitis, pseudomembranous
  • female
  • immunocompromised host
  • intestines
  • mice
  • mice, inbred C57BL
  • myeloid differentiation factor 88
  • spores, bacterial

Cite this

Lawley, T. D., Clare, S., Walker, A. W., Goulding, D., Stabler, R. A., Croucher, N., Mastroeni, P., Scott, P., Raisen, C., Mottram, L., Fairweather, N. F., Wren, B. W., Parkhill, J., & Dougan, G. (2009). Antibiotic treatment of Clostridium difficile carrier mice triggers a supershedder state, spore-mediated transmission, and severe disease in immunocompromised hosts. Infection and Immunity, 77(9), 3661-3669. https://doi.org/10.1128/IAI.00558-09