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Abstract
Cryptococcus neoformans is a fungal pathogen that infects the lungs and then often disseminates to the central nervous system, causing meningitis. How Cryptococcus is able to suppress host immunity and escape the antifungal activity of macrophages remains incompletely understood. We reported that the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase, promotes Cryptococcus virulence by regulating host-Cryptococcus interactions. Our recent studies demonstrated that the fbp1Δ mutant elicited superior protective Th1 host immunity in the lungs and that the enhanced immunogenicity of heat-killed fbp1Δ yeast cells can be harnessed to confer protection against a subsequent infection with the virulent parental strain. We therefore examined the use of heat-killed fbp1Δ cells in several vaccination strategies. Interestingly, the vaccine protection remains effective even in mice depleted of CD4+ T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that vaccinating mice with heat-killed fbp1Δ induces significant cross-protection against challenge with diverse invasive fungal pathogens, including C. neoformans, C. gattii, and Aspergillus fumigatus, as well as partial protection against Candida albicans Thus, our data suggest that the heat-killed fbp1Δ strain has the potential to be a suitable vaccine candidate against cryptococcosis and other invasive fungal infections in both immunocompetent and immunocompromised populations.IMPORTANCE Invasive fungal infections kill more than 1.5 million people each year, with limited treatment options. There is no vaccine available in clinical use to prevent and control fungal infections. Our recent studies showed that a mutant of the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in Cryptococcus neoformans, elicited superior protective Th1 host immunity. Here, we demonstrate that the heat-killed fbp1Δ cells (HK-fbp1) can be harnessed to confer protection against a challenge by the virulent parental strain, even in animals depleted of CD4+ T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that HK-fbp1 vaccination induces significant cross-protection against challenge with diverse invasive fungal pathogens. Thus, our data suggest that HK-fbp1 has the potential to be a broad-spectrum vaccine candidate against invasive fungal infections in both immunocompetent and immunocompromised populations.
Highlights
IMPORTANCE Invasive fungal infections kill more than 1.5 million people each year, with limited treatment options
Our recent study demonstrated that strong Th1 immune response developed in mice immunized with heat-killed fbp1Δ (HK-fbp1) cells
In the isotype control-treated mice, these cytokines were produced primarily by CD4ϩ cells (Fig. 3E). These results suggest that CD8ϩ T cells can compensate for the lack of CD4ϩ T cells in CD4ϩ T cell-depleted mice and are able to produce cytokines, such as IFN-␥, that are likely involved in heat-killed fbp1Δ cells (HK-fbp1) vaccine-induced protection of the host
Summary
IMPORTANCE Invasive fungal infections kill more than 1.5 million people each year, with limited treatment options. We demonstrate that the heat-killed fbp1Δ cells (HK-fbp1) can be harnessed to confer protection against a challenge by the virulent parental strain, even in animals depleted of CD4ϩ T cells This finding is important in the context of HIV/AIDS-induced immune deficiency. People with T cell immunodeficiency, such as HIV/AIDS patients, are highly susceptible to Cryptococcus infection, indicating the importance of cell-mediated immunity in host protection. C. neoformans mutant strains capable of inducing a highly protective Th1 response have been reported Several mutant strains, such as a strain overexpressing transcription factor Znf (ZNF2OE), a chitosan-deficient cda1⌬2⌬3⌬ strain, and a mutant lacking sterylglucosidase (sgl1⌬), have been identified as having increased immunogenicity in murine models. All of these exciting developments suggest that a vaccine against Cryptococcus or other invasive fungal infections is feasible
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