Impaired resistance and enhanced pathology during infection with a noninvasive, attaching-effacing enteric bacterial pathogen, Citrobacter rodentium, in mice lacking IL-12 or IFN-γ

Cameron P. Simmons, Nathalie S. Goncalves, Marjan Ghaem-Maghami, Mona Bajaj-Elliott, Simon Clare, Bianca Neves, Gad Frankel, Gordon Dougan, Thomas T. MacDonald

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126 Citations (Scopus)

Abstract

Mice infected with Citrobacter rodentium represent an excellent model in which to examine immune defenses against an attaching-effacing enteric bacterial pathogen. Colonic tissue from mice infected with C. rodentium harbors increased transcripts for IL-12 and IFN-γ and displays mucosal pathology compared with uninfected controls. In this study, the role of IL-12 and IFN-γ in host defense and mucosal injury during C. rodentium infection was examined using gene knockout mice. IL-12p40-/- and IFN-γ-/- mice were significantly more susceptible to mucosal and gut-derived systemic C. rodentium infection. In particular, a proportion of IL-12p40-/- mice died during infection. Analysis of the gut mucosa of IL-12p40-/- mice revealed an influx of CD4+ T cells and a local IFN-γ response. Infected IL-12p40-/- and IFN-γ-/- mice also mounted anti-Citrobacter serum and gut-associated IgA responses and strongly expressed inducible NO synthase (iNOS) in mucosal tissue, despite diminished serum nitrite/nitrate levels. However, iNOS does not detectably contribute to host defense against C. rodentium, as iNOS-/- mice were not more susceptible to infection. However, C57BL/6 mice infected with C. rodentium up-regulated expression of the mouse β-defensin (mBD)-1 and mBD-3 in colonic tissue. In contrast, expression of mBD-3, but not mBD-1, was significantly attenuated during infection of IL-12and IFN-γ-deficient mice, suggesting mBD-3 may contribute to host defense. These studies are among the first to examine mechanisms of host resistance to an attaching-effacing pathogen and show an important role for IL-12 and IFN-γ in limiting bacterial infection of the colonic epithelium.

Original languageEnglish
Pages (from-to)1804-1812
Number of pages9
JournalJournal of Immunology
Volume168
Issue number4
Publication statusPublished - 15 Feb 2002
Externally publishedYes

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