Colonization of the central nervous system as a key factor in the <i>Cryptococcus gattii</i> pathogenicity

The <i>Cryptococcus gattii</i> species complex is one of the main etiological agents of cryptococcosis, a fungal infection that affects the lungs and progresses to meningoencephalitis. Neurological infections caused by this species are associated with a higher incidence of cryptococcoma, sequelae, and relapse. Despite its clinical relevance, the mechanisms that sustain the infection and persistence of <i>C. gattii</i> in the central nervous system (CNS) are still poorly understood. In this study, we performed a comprehensive phenotypic characterization of the virulence of five <i>C. gattii</i> strains, focusing on the CNS infectious biology. Significant differences in virulence among the strains were found, highlighting intracellular survival within macrophages and growth in the CNS as determining factors of disease severity. The relative capsule size between 1-2, as opposed to a marked increase (> 2), was associated with increased virulence, a phenomenon we term optimized capsule enlargement. Considering the high energetic cost of capsule synthesis, this pattern favors the fungal reproductive fitness and replication within the host's tissues. These findings indicate that, in addition to the ability to reach the CNS, <i>C. gattii</i> needs to colonize it efficiently to cause severe clinical manifestations, with optimized capsule enlargement being a key factor for its survival in this microenvironment.