Cryptococcal dissemination to the central nervous system requires the vacuolar calcium transporter Pmc1

Cryptococcus neoformans is a basidiomycetous yeast and the cause of cryptococcosis in immunocompromised individuals. The most severe form of the disease is meningoencephalitis, which is one of the leading cause of death in HIV/AIDS patients. In order to access the central nervous system (CNS), C. neoformans relies on the activity of certain virulence factors such as urease, which allows transmigration through the blood–brain barrier (BBB). In the present study, we demonstrate that the calcium transporter Pmc1 enables C. neoformans to penetrate the CNS, since the pmc1 null mutant failed to infect and to survive within the brain parenchyma in a murine systemic infection model. To investigate potential alterations in transmigration pathways in these mutants, global expression profiling of the pmc1 mutant strain was undertaken and genes associated with urease, the Ca2+-calcineurin pathway and capsule assembly were identified as being differentially expressed. Also, a decrease in urease activity was observed in the calcium transporter null mutants. Finally, we demonstrate that the transcription factor Crz1 regulates urease activity, and that the Ca2+-calcineurin signaling pathway positively controls the transcription of calcium transporter genes and factors related to transmigration.