Characterization of a cell-mediated protective immune response to Cryptococcus neoformans in the murine central nervous system

Cryptococcus neoformans is a ubiquitous, encapsulated fungus and is the causative agent of cryptococcosis, a life-threatening opportunistic infection. The most severe manifestation of infection with C. neoformans is the involvement of the central nervous system (CNS), called cryptococcal meningoencephalitis. In immunocompromised individuals, cryptococcal meningoencephalitis is often fatal; but even when treated with anti-fungal drugs, the infection persists requiring life-long secondary prophylaxis. With better understanding of the mechanisms of protection from this pathogen, it may be possible to develop therapies to augment or bolster the immune response in immunosuppressed individuals so that they may be able to clear this otherwise fatal infection. In this study, a murine model is used to analyze the components and mechanisms of a protective response to C. neoformans in the CNS. A cell-mediated immune response is induced in the otherwise susceptible mouse by immunization with a cell-free antigen. Characterization of the protective response in the CNS is performed. Survival studies demonstrate that the immune response induced by peripheral immunization is capable of protecting the mouse from an otherwise lethal intracerebral inoculation of C. neoformans. This protection is associated with the production of Th1-type cytokines including interferon-gamma (IFNγ). The production of pro-inflammatory cytokines, are associated with protection, as is the early production of β chemokines. CD4 + T cells are required for the protective response; furthermore, adoptive transfer experiments demonstrate that CD4+ T cells are sufficient for some protection. CD4+ T cells are also required for optimal cytokine and chemokine production during the protective response; and in immunized mice, CD4+ T cells themselves produce IFNγ at the site of infection. Analyses of leukocytes in the brains of mice undergoing protective and non-protective responses to C. neoformans reveal that both resident macrophage-like cells and macrophages recruited to the CNS from the periphery may be involved in protection. Effector mechanisms may include the production of nitric oxide by inducible nitric oxide synthase (iNOS), which is upregulated in the protective response. This increased production of iNOS is CD4+ T cell-dependent. Overall, the analyses of this study support the hypothesis that a CD4+ T cell mediated response is capable of providing protection to cryptococcal infection of the murine CNS.