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Protection from Direct Cerebral Cryptococcus Infection by Interferon--Dependent Activation of Microglial Cells¹

Qing Zhou^*, Ruth A. Gault, Thomas R. Kozel and William J. Murphy^2,

^* Division of Blood and Marrow Transplantation, Cancer Center and Department of Pediatrics, MMC 109, University of Minnesota, Minneapolis, MN 55455; and Department of Microbiology and Immunology, University of Nevada, Reno, Reno, NV 89557

The brain represents a significant barrier for protective immune responses in both infectious disease and cancer. We have recently demonstrated that immunotherapy with anti-CD40 and IL-2 can protect mice against disseminated Cryptococcus infection. We now applied this immunotherapy using a direct cerebral cryptococcosis model to study direct effects in the brain. Administration of anti-CD40 and IL-2 significantly prolonged the survival time of mice infected intracerebrally with Cryptococcus neoformans. The protection was correlated with activation of microglial cells indicated by the up-regulation of MHC II expression on brain CD45^lowCD11b⁺ cells. CD4⁺ T cells were not required for either the microglial cell activation or anticryptococcal efficacy induced by this immunotherapy. Experiments with IFN- knockout mice and IFN-R knockout mice demonstrated that IFN- was critical for both microglial cell activation and the anticryptococcal efficacy induced by anti-CD40/IL-2. Interestingly, while peripheral IFN- production and microglial cell activation were observed early after treatment, negligible IFN- was detected locally in the brain. These studies indicate that immunotherapy using anti-CD40 and IL-2 can augment host immunity directly in the brain against C. neoformans infection and that IFN- is essential for this effect.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Service Grant CA095572-04.

² Address correspondence and reprint requests to William J. Murphy, University of Nevada, Department of Microbiology, Applied Research Facility, Room 342, Mail Stop 199, Reno, NV 89577. E-mail address: wmurphy{at}medicine.nevada.edu

³ Abbreviations used in this paper: BBB, blood brain barrier; DPBS, Dulbecco’s PBS; KO, knockout; GKO, IFN- KO; i.c., intracerebral; SAB, Sabouraud; WT, wild type.

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