Induction of Broad-spectrum Protective Immunity Against Disparate Serotypes of Cryptococcus

The Wormley laboratory studies the host immune response against the worldwide fungal pathogen, Cryptococcus. There are two main species of Cryptococcus that can be further categorized into four serotypes: C. neoformans comprises serotypes A and D and C. gattii comprises serotypes B and C. Although the majority of cryptococcal infections are caused by C. neoformans serotype A, an expansion of C. gattii in unique patient populations and environmental niches highlights the need to study the host immune response to multiple disparate serotypes of Cryptococcus. Studies herein reveal the heterogeneity of the host immune response across all four serotypes of Cryptococcus utilizing clinically relevant strains. Our studies demonstrate that for serotype C strains have low virulence, yet display high fungal burden with the absence of an immune response.

Studies from our laboratory have utilized an engineered serotype A strain of C. neoformans that secretes murine interferon-γ (IFN-γ), designated H99γ. Mice immunized with H99γ and subsequently challenged with WT H99 demonstrate 100% survival. Our studies sought to determine the efficacy of immunization with H99γ to elicit broad-spectrum protective immunity across multiple disparate Cryptococcus serotypes. Herein, we observed significantly increased survival rates and significantly decreased pulmonary fungal burden in H99γ immunized mice challenged with serotypes A, B, or D compared to heat-killed H99γ (HKH99γ) immunization. Prolonged protection afforded to mice challenged with serotypes B or D was dependent on CD4+ T cells and associated with the induction of a Th1-type response. Furthermore, our studies revealed potential subunit vaccine candidates that could provide broad-spectrum protection across serotypes of Cryptococcus.