The gamma interferon receptor is required for the protective pulmonary inflammatory response to Cryptococcus neoformans.
Mice with a null deletion mutation in the gamma interferon (IFN-gamma) receptor gene were used to study the role of IFN-gamma responsiveness during experimental pulmonary cryptococcosis. Cryptococcus neoformans was inoculated intratracheally into mice lacking the IFN-gamma receptor gene (IFN-gammaR-/-) and into control mice (IFN-gammaR+/+). The numbers of CFU in lung, spleen, and brain were determined to assess clearance; cytokines produced by lung leukocytes were measured, and survival curves were generated. In the present study, we demonstrate the following points. (i) IFN-gammaR-/- mice are markedly more susceptible to C. neoformans infection than IFN-gammaR+/+ mice. (ii) In the absence of IFN-gamma signaling, pulmonary CFU continue to increase over the course of infection, and the infection disseminates to the brain. (iii) In the absence of IFN-gamma receptor, recruitment of inflammatory cells in response to pulmonary cryptococcal infection is not impaired. (iv) At week 5 postinfection, IFN-gammaR-/- mice have recruited greater numbers of leukocytes into their lungs, with neutrophils, eosinophils, and lymphocytes accounting for this cellular increase. (v) IFN-gamma signaling is required for the development of a T1 over a T2 immune response in the lung following cryptococcal infection. These results indicate that in the absence of IFN- gamma responsiveness, even though the recruitment of pulmonary inflammatory cells is not impaired and the secretion of IFN-gamma is not affected, IFN-gammaR-/- mice do not have the ability to resolve the cryptococcal infection. In conclusion, our data suggest that proper functional IFN-gamma signaling, possibly through a mechanism which inhibits the potentially disease-promoting T2 response, is required for mice to confine the cryptococcal infection.
Chen
Gwo-Hsiao
GH
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, 6301 MSRB III-Box 0642, University of Michigan Medical School, 1150 W. Medical Ctr. Dr., Ann Arbor, MI 48109-0642, USA. gchen@umich.edu
McDonald
Roderick A
RA
Wells
Jason C
JC
Huffnagle
Gary B
GB
Lukacs
Nicholas W
NW
Toews
Galen B
GB
D000818:Animals; D002478:Cells, Cultured; D003453:Cryptococcosis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D003455:Cryptococcus neoformans / Q000472:pathogenicity*; D017353:Gene Deletion; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D051379:Mice; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor
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