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Infection and Immunity, May 2002, p. 2591-2597, Vol. 70, No. 5
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.5.2591-2597.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Enhanced Disease Severity in Helicobacter pylori-Infected Mice Deficient in Fas Signaling

Nicola L. Jones,1,2* Andrew S. Day,2 Hilary Jennings,2 Patrick T. Shannon,3 Esther Galindo-Mata,2 and Philip M. Sherman2,3

Departments of Physiology,1 Pediatrics,2 Laboratory Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada3

Received 6 September 2001/ Returned for modification 28 November 2001/ Accepted 22 January 2002

Recent evidence suggests that immune-mediated gastric epithelial cell apoptosis through Fas-Fas ligand interactions participates in Helicobacter pylori disease pathogenesis. To define the role of Fas signaling in vivo, H. pylori strain SS1 infection in C57BL/6 mice was compared to that in mice deficient in the Fas ligand (gld). gld mice had a degree of gastritis similar to that of C57BL/6 mice after 6 weeks (gastritis score, 5.2 ± 0.6 [mean ± standard error] versus 3.5 ± 0.8) and 12 weeks (4.0 ± 0.7 versus 3.4 ± 0.5) of infection. Bacterial colonization was comparable in each group of mice at 12 weeks of infection (2.1 ± 0.3 versus 1.6 ± 0.3 for gld and C57BL/6, respectively; the difference is not significant). Sixty-seven percent of H. pylori-infected gld mice displayed atrophic changes in the gastric mucosa, compared with 37% of infected C57BL/6 mice, at 12 weeks. In addition, atrophic changes were more severe in H. pylori-infected gld mice (P < 0.05). Splenocytes isolated from H. pylori-infected C57BL/6 mice had a twofold increase in production of the Th1 cytokine gamma interferon (IFN-{gamma}) in response to H. pylori antigens at both 6 and 12 weeks compared to controls (143 ± 65 versus 69 ±26 pg/ml and 336 ± 73 versus 172 ± 60, respectively). In contrast, there was a lack of detectable IFN-{gamma} in gld mice infected with the bacterium. H. pylori-infected C57BL/6 mice had increased epithelial cell apoptosis compared with sham-infected C57BL/6 mice (35.0 ± 8.9 versus 12.3 ± 6.9; P < 0.05). Epithelial cell apoptosis did not differ between H. pylori-infected and control gld mice (5.2 ± 1.6 versus 6.5 ± 2.9 [not significant]). These data demonstrate that mice with mutations in the Fas ligand develop more severe premalignant mucosal changes in response to infection with H. pylori in association with both an impaired gastric epithelial cell apoptotic response and IFN-{gamma} production. The Fas death pathway modulates disease pathophysiology following murine infection with H. pylori. Deregulation of the Fas pathway could be involved in the transition from gastritis to gastric cancers during H. pylori infection.

* Corresponding author. Mailing address: Division of GI/Nutrition, Room 8409, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Phone: (416) 813-7734. Fax: (416) 813-6531. E-mail: nicola.jones{at}sickkids.ca.

Editor: J. D. Clements

Infection and Immunity, May 2002, p. 2591-2597, Vol. 70, No. 5
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.5.2591-2597.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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