Cryptococcosis is primarily a disease of the lung and central nervous system and is the commonest cause of fungal meningitis, which is fatal if untreated. Pathogenic species in the Cryptococcus complex, C. neoformans and C. gattii, invade host tissue via production of two enzymes, phospholipase B (PLB1) and urease.
PLB1 has been studied in our laboratory for many years. Post-inhalation of infectious propagules, it facilitates invasion of lung tissue. It is also essential for egress of cryptococci from the lung to the circulation, for establishment of CNS disease and for extrusion from macrophage phago-lysosomes. Recently we have noted accumulation of PLB1 at bud-necks and failure of separation of daughter from parent cells following deletion of a critical secretory pathway enzyme, SEC14, suggesting that PLB1 is also involved in cell membrane/wall remodelling during replication.
Production of cryptococcal virulence factors is regulated by signalling pathways, which include calcineurin and Ras. We have recently begun to elucidate the role of and additional Plc1/IPK pathway. To date we have shown using gene deletion/reconstitution and inhibitor studies that PLB1 secretion is mediated independently through the calcineurin and Plc1/IPK pathways.
Though PLB1 is one of two enzymes proven to effect invasion of cryptococci into host tissue, it is only one of several determinants in the overall fungal virulence composite. Much remains to be determined about its mode of secretion and the complexity of the signaling pathways that regulate its production. Elucidation of these pathways may provide new targets for antifungal drug development.