Colonization of the central nervous system as a key factor in the Cryptococcus gattii pathogenicity

The Cryptococcus gattii species complex is one of the main etiological agents of cryptococcosis, a fungal infection that primarily affects the lungs and can progress to meningoencephalitis. Despite its clinical relevance, the mechanisms that sustain the infection and persistence of C. gattii in the central nervous system (CNS) are still poorly understood. Therefore, we performed a comprehensive phenotypic virulence characterization of strains of the C. gattii complex, aiming to elucidate aspects of its infectious biology in the CNS. In vitro, we identified significant differences between the strains in terms of reproductive fitness, melanization, laccase activity, and capsule size. In a murine model, we observed a morphological dynamic change characterized by the predominance of small cells at the beginning of the infection and a subsequent increase in the size of the polysaccharide capsule in all strains, regardless of the virulence profile. Considering that the capsule synthesis is a very energy-dispendious process, a medium relative capsule size (1-2), and not a large one (>2) was related to higher virulence and we named it as optimized capsule enlargement. More virulent strains presented (i) greater resistance to the fungicidal macrophage’s activity, (ii) optimized capsule enlargement in the CNS, and (iii) greater fitness in the brain. These findings reinforce that, in addition to the ability to reach the CNS, C. gattii needs to be able to colonize it to cause severe clinical manifestations. From this perspective, the optimized increase of the polysaccharide capsule is a key factor for survival in the CNS.