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The Journal of Immunology, 2005, 174: 1746-1750.
Copyright © 2005 by The American Association of Immunologists

IFN-{gamma} at the Site of Infection Determines Rate of Clearance of Infection in Cryptococcal Meningitis1

Asna A. Siddiqui2,*, Annemarie E. Brouwer2,*,{dagger},{ddagger}, Vannaporn Wuthiekanun{dagger}, Shabbar Jaffar§, Robin Shattock*, Diane Irving*, Joanna Sheldon*, Wirongrong Chierakul{dagger}, Sharon Peacock{dagger},¶, Nicholas Day{dagger},¶, Nicholas J. White{dagger},¶ and Thomas S. Harrison3,*

* Departments of Infectious Diseases and Immunology, St. George’s Hospital Medical School, London, United Kingdom; {dagger} Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; {ddagger} Department of Internal Medicine and Infectious Diseases, University Medical Centre, Nijmegen, The Netherlands; § London School of Hygiene and Tropical Medicine, London, United Kingdom; and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-{gamma}, TNF-{alpha}, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-{alpha}, IFN-{gamma}, and IL-6 levels and baseline cryptococcal CFU. Log IFN-{gamma}, G-CSF, TNF-{alpha}, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-{gamma} remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-{gamma} secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-{gamma} in the treatment of refractory HIV-associated cryptococcosis.




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