Citrobacter rodentium Infection in Mice Elicits a Mucosal Th1 Cytokine Response and Lesions Similar to Those in Murine Inflammatory Bowel Disease

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Infection and Immunity, June 1999, p. 3031-3039, Vol. 67, No. 6
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Citrobacter rodentium Infection in Mice Elicits a Mucosal Th1 Cytokine Response and Lesions Similar to Those in Murine Inflammatory Bowel Disease

Lisa M. Higgins,¹ Gad Frankel,² Gill Douce,² Gordon Dougan,² and Thomas T. MacDonald¹^,^*

Department of Paediatric Gastroenterology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, St. Bartholomew's Hospital, London EC1A 7BE,¹ and Department of Biochemistry, Imperial College of Science, Technology and Medicine, London SW7 2AZ,² United Kingdom

Received 23 December 1998/Returned for modification 24 February 1999/Accepted 30 March 1999

Citrobacter rodentium is a classically noninvasive pathogen of mice that is similar to enteropathogenic Escherichia coli (EPEC)in man. Following oral infection of young mice, the organism colonizesthe distal colon, and within 1 week the colonic mucosa doublesin thickness and there is massive epithelial cell hyperplasia.Since T-cell responses in mouse models of inflammatory bowel disease(IBD) also cause epithelial hyperplasia, we have investigatedthe possibility that C. rodentium promotes similar T-cell responsesin the mucosa, thereby increasing epithelial shedding, transmission,and replication of the organism. Beginning 6 days after infection,bacteria were observed to be in close association with the epithelialsurface and were also visible scattered throughout the laminapropria and in the submucosa. There was a CD3⁺-cell infiltrate into the colonic lamina propria and epitheliumas well as mucosal thickening and crypt hyperplasia. The majorityof CD3⁺ cells were CD4⁺ and were not $gamma$ $delta$ ⁺. Reverse transcription-PCR analysis of cytokines also revealeda highly polarized Th1 response (interleukin-12, gamma interferon,and tumor necrosis factor alpha) in the mucosa and a large increasein the epithelial cell mitogen keratinocyte growth factor. Noneof the changes were seen in mice inoculated with bacteria lackingintimin (which is necessary for colonization), but they were seenin mice inoculated with C. rodentium complemented with intiminfrom EPEC. This is the first example of a classically noninvasivebacterial pathogen which elicits a strong mucosal Th1 responseand which produces pathology similar to that seen in mouse modelsof IBD, which is also characterized by a strong Th1 response.These results also suggest that the colonic mucosa responds ina stereotypic way to Th1responses.

^* Corresponding author. Mailing address: Department of Paediatric Gastroenterology, St. Bartholomew's and the Royal London Schoolof Medicine and Dentistry, Suite 31, Dominion House, 59 BartholomewClose, London EC1A 7BE, United Kingdom. Phone: 44(0)171 601 8160.Fax: 44(0)171 600 5901. E-mail: t.t.macdonald{at}mds.qmw.ac.uk.

Infection and Immunity, June 1999, p. 3031-3039, Vol. 67, No. 6
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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