Impaired resistance and enhanced pathology during infection with a noninvasive, attaching-effacing enteric bacterial pathogen, Citrobacter rodentium, in mice lacking IL-12 or IFN-gamma.
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-gamma and displays mucosal pathology compared with uninfected controls. In this study, the role of IL-12 and IFN-gamma in host defense and mucosal injury during C. rodentium infection was examined using gene knockout mice. IL-12p40(-/-) and IFN-gamma(-/-) 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-gamma response. Infected IL-12p40(-/-) and IFN-gamma(-/-) 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 beta-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-12- and IFN-gamma-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-gamma in limiting bacterial infection of the colonic epithelium.
Simmons
Cameron P
CP
Department of Biochemistry, Center for Molecular Microbiology and Infection, Imperial College, South Kensington, London, United Kingdom. csimmons@hcm.vnn.vn
Goncalves
Nathalie S
NS
Ghaem-Maghami
Marjan
M
Bajaj-Elliott
Mona
M
Clare
Simon
S
Neves
Bianca
B
Frankel
Gad
G
Dougan
Gordon
G
MacDonald
Thomas T
TT
D000284:Administration, Oral; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis; D000942:Antigens, Bacterial / Q000276:immunology; D001422:Bacterial Adhesion; D016971:Citrobacter freundii / Q000302:isolation & purification / Q000472:pathogenicity; D003106:Colon / Q000276:immunology / Q000473:pathology; D003108:Colonic Diseases / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D015169:Colony Count, Microbial; D004756:Enterobacteriaceae Infections / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D005260:Female; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis; D023083:beta-Defensins / Q000096:biosynthesis / Q000235:genetics
D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D012333:RNA, Messenger; D023083:beta-Defensins; D018664:Interleukin-12; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse