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Infection and Immunity, May 2003, p. 2534-2541, Vol. 71, No. 5
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.5.2534-2541.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Development of an Interleukin-12-Deficient Mouse Model That Is Permissive for Colonization by a Motile KE26695 Strain of Helicobacter pylori

Paul S. Hoffman,1,2* Neeraj Vats,1 Donna Hutchison,3 Jared Butler,3 Kenneth Chisholm,1 Gary Sisson,1 Ausra Raudonikiene,1 Jean S. Marshall,1,4 and Sander J. O. Veldhuyzen van Zanten3

Department of Microbiology and Immunology, Divisions of,1 Infectious Diseases,2 Gastroenterology, Department of Medicine,3 Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada4

Received 19 August 2002/ Returned for modification 13 November 2002/ Accepted 10 February 2003

The identification of genes associated with colonization and persistence of Helicobacter pylori in the gastric mucosa has been limited by the lack of robust animal models that support infection by strains whose genomes have been completely sequenced. Here we report that an interleukin-12 (IL-12)-deficient mouse (IL-12-/- p40 subunit knockout in C57BL/6 mouse) is permissive for infection by a motile variant (KE88-3887) of The Institute For Genomic Research-sequenced strain (KE26695) of H. pylori. The IL-12-deficient mouse was also more permissive for colonization by the mouse-colonizing Sydney 1 strain of H. pylori than were wild-type C57BL/6 mice. Differences in colonization efficiency were demonstrated by mouse challenge with SS1 strains containing loss-of-function mutations in two genes (hspR and hrcA), whose products negatively regulate several heat shock genes. At 5 weeks postinfection, double-knockout mutants (SS1 hspR hrcA) efficiently colonized IL-12-deficient mice (5 of 5 animals compared to 4 of 10 for C57BL6 mice) and bacterial counts were higher in stomachs of IL-12-deficient mice (106 versus 105 CFU/g of stomach, respectively). IL-12-deficient mice were efficiently colonized by KE88-3887 (29 of 30), but not by nonmotile KE26695, and bacterial numbers (104 to 105 CFU/g of stomach) were unchanged over an 8-week period postinfection. In contrast, C57BL/6 mice were inefficiently colonized by KE88-3887 (8 of 20 animals with bacterial loads at the limit of detection, ~103 CFU/g), and infection did not persist much beyond 5 weeks. Cytokine responses (tumor necrosis factor alpha and gamma interferon), pathology, and antral-predominant infection were indistinguishable between IL-12-deficient and C57BL/6 mice. The increased permissiveness of the IL-12-deficient mouse for infection with H. pylori should facilitate whole-genome-based strategies to study genes associated with virulence and immune modulation.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Sir Charles Tupper Medical Bldg, Rm. 7P, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada. Phone: (902) 494-3889. Fax: (902) 494-5125. E-mail: phoffman{at}tupdean2.med.dal.ca.

Editor: B. B. Finlay

Infection and Immunity, May 2003, p. 2534-2541, Vol. 71, No. 5
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.5.2534-2541.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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