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Infection and Immunity, April 2004, p. 2338-2349, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.2338-2349.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Cytokine and Inducible Nitric Oxide Synthase mRNA Expression during Experimental Murine Cryptococcal Meningoencephalitis

Claudia M. L. Maffei,1,2,3,4 Laurence F. Mirels,2,3,4 Raymond A. Sobel,5,6 Karl V. Clemons,2,3,4* and David A. Stevens2,3,4

Department of Cellular and Molecular Biology, School of Medicine of Ribeirão Preto of the University of São Paulo, Ribeirão Preto, São Paulo 14049-900 Brazil,1 Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center,2 California Institute for Medical Research, San Jose, California 95128,3 Division of Infectious Diseases and Geographic Medicine, Department of Medicine,4 Department of Pathology, Stanford University School of Medicine, Stanford, California 94305,5 Palo Alto VA Health Care System, Palo Alto, California 943046

Received 14 July 2003/ Returned for modification 8 August 2003/ Accepted 12 January 2004

The immune events that take place in the central nervous system (CNS) during cryptococcal infection are incompletely understood. We used competitive reverse transcription-PCR to delineate the time course of the local expression of mRNAs encoding a variety of cytokines and inducible nitric oxide synthase (iNOS) during progressive murine cryptococcal meningoencephalitis and assessed the CNS inflammatory response using immunohistochemistry. Interleukin 18 (IL-18), transforming growth factor ß1, and IL-12p40 mRNAs were constitutively expressed in the brains of infected and uninfected mice; IL-2 mRNA was not detected at any time. Increased levels of transcripts corresponding to IL-1{alpha}, tumor necrosis factor alpha (TNF-{alpha}), and iNOS were detected as early as day 1 postinfection, with TNF-{alpha} rising by ~30-fold and iNOS increasing by ~5-fold by day 7. Each remained at these levels thereafter. IL-4, IL-6, and gamma interferon transcripts were detected on day 5, and IL-1ß and IL-10 transcripts were detected beginning on day 7. Once detected, each remained at a relatively constant level through 28 days of infection. This cytokine profile does not suggest a polarized Th1 or Th2 response. Immunohistochemistry did not reveal inflammatory infiltrates before day 7, despite the presence of cryptococci. Intraparenchymal abscesses with inflammatory cells in their peripheries were found beginning on day 10. The infiltrates were comprised primarily of cells expressing CD4, CD8, or CD11b; low numbers of cells expressing CD45R/B220 were also present. The persistence of Cryptococcus observed in the CNS may result from an ineffective immune response, perhaps owing to an insufficient anticryptococcal effector function of endogenous glial cells resulting from competing pro- and anti-inflammatory cytokines. These data detail the immune response in the brain and could be important for the future design of specific immunomodulatory therapies for this important opportunistic infection.

* Corresponding author. Mailing address: Department of Medicine, Division of Infectious Diseases, Santa Clara Valley Medical Center, 751 South Bascom Ave., San Jose, CA 95128-2699. Phone: (408) 998-4557. Fax: (408) 998-2723. E-mail: clemons{at}cimr.org.

Editor: T. R. Kozel

Infection and Immunity, April 2004, p. 2338-2349, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.2338-2349.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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