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Role of Interleukin-4 in Resistance to Cryptococcus neoformans Infection

Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Address correspondence to: Rebecca Blackstock, Ph.D., Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190. E-mail: becky-blackstock{at}ouhsc.edu

The role of interleukin (IL)-4 in cryptococcal disease was studied in IL-4 knockout (IL-4KO) and wild-type (WT) mice infected with Cryptococcus neoformans isolates that vary widely in their virulence. Delayed-type hypersensitivity responses were reduced in IL-4KO mice following primary infection with either isolate. Splenic T helper 1 (Th1) cytokine responses were increased in the IL-4KO mice infected with the weakly virulent isolate (184A) but did not change during infection with the highly virulent isolate (NU-2). Th2 cytokine responses (IL-5, IL-10) were downregulated in the IL-4KO mice infected with either isolate. Survival after primary infection with either isolate was not influenced by the absence of IL-4. Fewer colony-forming units were found in the lungs of 184A-infected, IL-4KO mice as compared to WT mice, suggesting that some immunity had developed. IL-4KO mice, primed with small doses of cryptococcal antigen (CneF), had significantly enhanced delayed-type hypersensitivity responses after intravenous infection with 184A and were more resistant to infection compared with WT mice. Increased expression of IL-5 with decreased interferon- contributed to the inability of primed WT mice to resist infection with 184A. Enhanced immunity in the primed IL-4KO mice was reflected in a more moderate increase in IL-5 and IL-10 with maintenance of interferon- levels.

Abbreviations: colony-forming units, cfu • cell-mediated immunity, CMI • cryptococcal culture filtrate antigen, CneF • delayed-type hypersensitivity, DTH • enzyme-linked immunosorbent assay, ELISA • fetal bovine serum, FBS • Hanks' balanced salt solution, HBSS • interferon-, IFN- • interleukin, IL • IL-4–deficient mice, IL-4KO • sterile physiological saline solution, SPSS • T helper 1, Th1 • T helper 2, Th2 • wild-type, WT

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