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Infection and Immunity, November 2002, p. 6424-6435, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.6424-6435.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Modulation of Inducible Nitric Oxide Synthase Expression by the Attaching and Effacing Bacterial Pathogen Citrobacter rodentium in Infected Mice

Bruce A. Vallance,1 Wanyin Deng,1 Myriam De Grado,1 Crystal Chan,1 Kevan Jacobson,2 and B. Brett Finlay1*

Biotechnology Laboratory, University of British Columbia,1 Department of Pediatrics, Division of Gastroenterology, British Columbia Children's Hospital, Vancouver, British Columbia, Canada V6T 1Z32

Received 14 May 2002/ Returned for modification 20 June 2002/ Accepted 8 August 2002

Citrobacter rodentium belongs to the attaching and effacing family of enteric bacterial pathogens that includes both enteropathogenic and enterohemorrhagic Escherichia coli. These bacteria infect their hosts by colonizing the intestinal mucosal surface and intimately attaching to underlying epithelial cells. The abilities of these pathogens to exploit the cytoskeleton and signaling pathways of host cells are well documented, but their interactions with the host's antimicrobial defenses, such as inducible nitric oxide synthase (iNOS), are poorly understood. To address this issue, we infected mice with C. rodentium and found that iNOS mRNA expression in the colon significantly increased during infection. Immunostaining identified epithelial cells as the major source for immunoreactive iNOS. Finding that nitric oxide (NO) donors were bacteriostatic for C. rodentium in vitro, we examined whether iNOS expression contributed to host defense by infecting iNOS-deficient mice. Loss of iNOS expression caused a small but significant delay in bacterial clearance without affecting tissue pathology. Finally, immunofluorescence staining was used to determine if iNOS expression was localized to infected cells by staining for the C. rodentium virulence factor, translocated intimin receptor (Tir), as well as iNOS. Interestingly, while more than 85% of uninfected epithelial cells expressed iNOS, fewer than 15% of infected (Tir-positive) cells expressed detectable iNOS. These results demonstrate that both iNOS and intestinal epithelial cells play an active role in host defense during C. rodentium infection. However, the selective expression of iNOS by uninfected but not infected cells suggests that this pathogen has developed mechanisms to locally limit its exposure to host-derived NO.

* Corresponding author. Mailing address: Biotechnology Laboratory, Room 237, Wesbrook Building, 6174 University Blvd., University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Phone: 604-822-2210. Fax: 604-822-9830. E-mail: bfinlay{at}interchange.ubc.ca.

Editor: A. D. O'Brien

Infection and Immunity, November 2002, p. 6424-6435, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.6424-6435.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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