The F-Box Protein Fbp1 Shapes the Immunogenic Potential of Cryptococcus neoformans

Abstract

Cryptococcus neoformans is the main etiologic agent of cryptococcal meningitis and causes a significant number of deadly infections per year. Although it is well appreciated that host immune responses are crucial for defense against cryptococcosis, our understanding of factors that control the development of effective immunity to this fungus remains incomplete. In previous studies, we identified the F-box protein Fbp1 as a novel determinant of C. neoformans virulence. In this study, we found that the hypovirulence of the fbp1Δ mutant is linked to the development of a robust host immune response. Infection with the fbp1Δ mutant induces a rapid influx of CCR2⁺ monocytes and their differentiation into monocyte-derived dendritic cells (mo-DCs). Depletion of CCR2⁺ monocytes and their derivative mo-DCs resulted in impaired activation of a protective inflammatory response and the rapid death of mice infected with the fbp1Δ mutant. Mice lacking B and T cells also developed fungal meningitis and succumbed to infection with the fbp1Δ mutant, demonstrating that adaptive immune responses to the fbp1Δ mutant help to maintain the long-term survival of the host. Adaptive immune responses to the fbp1Δ mutant were characterized by enhanced differentiation of Th1 and Th17 CD4⁺ T cells together with diminished Th2 responses compared to the H99 parental strain. Importantly, we found that the enhanced immunogenicity of fbp1Δ mutant yeast cells can be harnessed to confer protection against a subsequent infection with the virulent H99 parental strain. Altogether, our findings suggest that Fbp1 functions as a novel virulence factor that shapes the immunogenicity of C. neoformansIMPORTANCECryptococcus neoformans is the most common cause of deadly fungal meningitis, with over 270,000 infections per year. Immune responses are critically required for the prevention of cryptococcosis, and patients with impaired immunity and low CD4⁺ T cell numbers are at high risk of developing these deadly infections. Although it is well appreciated that the development of protective immunity is shaped by the interactions of the host immune system with fungal cells, our understanding of fungal products that influence this process remains poor. In this study, we found that the activity of F-box protein 1 (Fbp1) in highly virulent C. neoformans clinical strain H99 shapes its immunogenicity and thus affects the development of protective immune responses in the host. The identification of this new mechanism of virulence may facilitate the future development of therapeutic interventions aimed at boosting antifungal host immunity.

Keywords: Cryptococcus neoformans; T cells; immunization; monocytes.