Paths to pathogenicity: exploring the diversity and evolution of Cryptococcus neoformans

Pathogenicity has evolved repeatedly in the fungal kingdom. Yet, our understanding of the evolutionary transitions that drive pathogenic species to emerge remains limited. The fungal pathogen, Cryptococcus neoformans and its relatives within the Cryptococcus genus, provide an ideal model system to better understand the evolution of virulence across fungal species. As a globally-distributed fungus, C. neoformans has adapted to numerous environments, resulting in dramatic phenotypic and genotypic diversity across isolates. Furthermore, the density of species within this genus and clear emergence of a single pathogenic lineage provide a compelling case study for mapping how this trait evolved. Recent efforts have demonstrated how exploiting naturally existing diversity across strains and species provides a powerful lens to examine the evolutionary paths to virulence. In this review, we discuss how the genotypic and phenotypic heterogeneity in C. neoformans clinical and environmental isolates can help us define different trajectories towards virulence. We then describe how the evolution of this species is being studied and how data across studies can be integrated. Lastly, we highlight major outstanding questions and provide perspectives on the ways novel methodologies might be applied to provide new insight into the evolution of this critical fungal pathogen.