Ras links cellular morphogenesis to virulence by regulation of the MAP kinase and cAMP signalling pathways in the pathogenic fungus Candida albicans

The pathogenic fungus Candida albicans is capable of responding to a wide v ariety of environmental cues with a morphological transition from a budding yeast to a polarized filamentous form. We demonstrate that the Ras homolog ue of C. albicans, CaRas1p, is required for this morphological transition a nd thereby contributes to the development of pathogenicity. However, CaRas1 p is not required for cellular viability. Deletion of both alleles of the C aRAS1 gene caused in vitro defects in morphological transition that were re versed by either supplementing the growth media with cAMP or overexpressing components of the filament-inducing mitogen-activated protein (MAP) kinase cascade. The induction of filament-specific secreted aspartyl proteinases encoded by the SAP4-6 genes was blocked in the mutant cells. The defects in filament formation were also observed in situ after phagocytosis of C. alb icans cells in a macrophage cell culture assay and, in vivo, after infectio n of kidneys in a mouse model for systemic candidiasis. In the macrophage a ssay, the mutant cells were less resistant to phagocytosis. Moreover, the d efects in filament formation were associated with reduced virulence in the mouse model. These results indicate that, in response to environmental cues , CaRas1p is required for the regulation of both a MAP kinase signalling pa thway and a cAMP signalling pathway. CaRas1p-dependent activation of these pathways contributes to the pathogenicity of C. albicans cells through the induction of polarized morphogenesis. These findings elucidate a new medica lly relevant role for Ras in cellular morphogenesis and virulence in an imp ortant human infectious disease.