Subunits of adaptor protein complex-1 make distinct contributions to the virulence of Cryptococcus neoformans

Cryptococcal meningoencephalitis is among the most prevalent invasive fungal diseases, posing a threat to immunocompromised individuals and representing a growing global health concern. The mechanisms of cryptococcal trafficking of virulence factors during disease are incompletely understood. Adaptor protein (AP) complexes play crucial roles in intracellular trafficking by orchestrating the sorting of macromolecular cargo and serving as essential components of the endocytic and secretory pathways. In a recent study, we demonstrated that Cryptococcus neoformans cells lacking the AP-1 complex subunits exhibit impaired elaboration of virulence factors and fail to survive in the harsh conditions of the macrophage phagolysosome. Although we characterized the phenotypes of AP-1 deficient cells in vitro, the contribution of this complex to pathogenesis remains unexplored. In this study, we show that mutants deficient in AP-1 complex subunits are either avirulent or exhibit attenuated virulence in a murine inhalational model. Loss of the small subunit resulted in the formation of granuloma-like lesions in mouse lungs with early containment of infection but eventual mortality, whereas mutants lacking the large subunits were rapidly cleared by mice. The delayed onset of disease in mice caused by mutants lacking the small subunit was marked by delayed weight loss and increased respiration rate, yet the mutant exhibited enhanced dissemination during late-stage infection, coinciding with waning immune responses and elevated collagen deposition. These findings demonstrate that deficiencies in the AP-1 complex impair C. neoformans virulence, reveal distinct roles for individual subunits, and identify the complex as a potential target for therapeutic intervention in cryptococcosis.