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Infection and Immunity, March 2005, p. 1788-1796, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1788-1796.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Gamma Interferon Receptor Is Required for the Protective Pulmonary Inflammatory Response to Cryptococcus neoformans

Gwo-Hsiao Chen,1* Roderick A. McDonald,1 Jason C. Wells,1 Gary B. Huffnagle,1,2 Nicholas W. Lukacs,3 and Galen B. Toews1

Division of Pulmonary and Critical Care, Department of Internal Medicine,1 Department of Microbiology and Immunology,2 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan3

Received 17 September 2004/ Returned for modification 12 October 2004/ Accepted 30 October 2004

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-{gamma}R–/–) and into control mice (IFN-{gamma}R+/+). 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-{gamma}R–/– mice are markedly more susceptible to C. neoformans infection than IFN-{gamma}R+/+ 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-{gamma}R–/– 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-{gamma}R–/– 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.

* Corresponding author. Mailing address: Division of Pulmonary and Critical Care Medicine, 6301 MSRB III—Box 0642, University of Michigan Medical School, 1150 W. Medical Ctr. Dr., Ann Arbor, MI 48109-0642. Phone: (734) 647-9971. Fax: (734) 764-4556. E-mail: gchen{at}umich.edu.

Editor: T. R. Kozel

Infection and Immunity, March 2005, p. 1788-1796, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1788-1796.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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