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Infection and Immunity, December 2003, p. 7129-7139, Vol. 71, No. 12
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.12.7129-7139.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Critical Roles for stx2, eae, and tir in Enterohemorrhagic Escherichia coli-Induced Diarrhea and Intestinal Inflammation in Infant Rabbits

Jennifer M. Ritchie,1 Cheleste M. Thorpe,1 Arlin B. Rogers,2 and Matthew K. Waldor1*

Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, and Howard Hughes Medical Institute, Boston, Massachusetts 02111,1 Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 021392

Received 15 August 2003/ Accepted 4 September 2003

Enterohemorrhagic Escherichia coli (EHEC) is a group of food-borne pathogens that can cause diarrhea, colitis, and the hemolytic uremic syndrome (HUS). The importance of several of the proposed EHEC virulence factors lacks experimental verification in animal models. The limitations of current animal models led us to reexamine the infant rabbit model for the study of EHEC pathogenicity. Here, we report that intragastric inoculation of a Shiga toxin 2 (Stx2)-producing E. coli O157:H7 clinical isolate into infant rabbits led to severe diarrhea and intestinal inflammation but no signs of HUS. We constructed a set of isogenic derivatives of this isolate with deletions in several putative virulence genes, including stx2, eae, tir, and ehxA, to investigate the contribution of individual virulence factors to EHEC pathogenicity. stx2 increased the severity and duration of EHEC-induced diarrhea. Furthermore, although stx2 had no role in EHEC intestinal colonization nor was it required for EHEC-induced inflammation, stx2 altered how the host responded to EHEC infection by promoting heterophilic infiltration of the colonic epithelium and lamina propria. Intragastric inoculation of purified Stx2 also induced inflammation and diarrhea in this model. Diarrhea and intestinal inflammation were also dependent on EHEC colonization, as EHEC derivatives with deletions in eae and tir did not colonize, form attaching and effacing lesions, or develop clinical signs of disease. Our studies indicate that infant rabbits are a useful model for investigation of the intestinal stage of EHEC pathogenesis and suggest that Shiga toxin may play a critical role in causing diarrhea and inflammation in patients infected with EHEC.

* Corresponding author. Mailing address: Department of Microbiology, Tufts University School of Medicine, 136 Harrison Ave., Boston MA 02111. Phone: (617) 636 2730. Fax: (617) 636 2723. E-mail: matthew.waldor{at}tufts.edu.

Editor: A. D. O'Brien

Infection and Immunity, December 2003, p. 7129-7139, Vol. 71, No. 12
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.12.7129-7139.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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