Cryptococcal meningoencephalitis is caused by Cryptococcus neoformans, an encapsulated fungus which is ubiquitous in urban environments. Infection is thought to occur via the respiratory system following inhalation of C. neoformans. The respiratory infection is often transient or inapparent, but subsequent systemic cryptococcoses often result in cryptococcal meningoencephalitis, the classical presentation of cryptococcoses. Cryptococcal meningitis is incurable in patients with AIDS, despite antifungal treatments. The hypothesis to be tested in this proposal is that microglia and astrocytes can function as effector cells in cryptococcal meningoencephalitis and that modulation of their effector function by cytokines and opsonins may modify the course and the outcome of cryptococcal infection. The first Specific Aim will study the interaction of microglia with C. neoformans, and the role of cytokines and capspule-specific antibodies in modifying the interaction. Particular emphasis will be placed on the role of mAbs developed in this Institution that have been shown to offer protective immunity in murine infection. In the second Specific Aim, the fate of C. neoformans- infected microglia will be determined, since evidence suggests phagocyte killing as a novel mechanism of host injury induced by C. neoformans. The hypotheses to be tested include that the mode of phagocyte death can determine the fate of organisms. By defining the host cell parameters that successfully lead to killing of C. neoformans, the applicants hope to be able to optimize the therapy. In the third Specific Aim, interactions of C. neoformans and HIV-1 in microglia will be determined. Since most patients with cryptococcal meningitis also harbor HIV-1 virus in the CNS, it will be of paramount importance to examine the role of HIV-1 in modifying antifungal effector mechanisms exerted by microglia. In the fourth Specific Aim, they will test the hypothesis that C. neoformans alter the cytokine and chemokine milieu in the CNS which, in turn, modulates antifungal and antiviral activity of microglia and astrocytes. The last Specific Aim will define the role of nitric oxide synthase in anticryptococcal activity in human CNS and in culture. Specifically, they will determine if cytokine-activated astrocytes can synergize with microglia to promote intracellular killing by providing nitric oxide. These experiments will use human brain cells thus permitting the direct correlation of the observed results to potential therapeutic intervention in man.
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