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 variety of environmental cues with a morphological transition from a budding yeast to a polarized filamentous form. We demonstrate that the Ras homologue of C. albicans, CaRas1p, is required for this morphological transition and thereby contributes to the development of pathogenicity. However, CaRas1p is not required for cellular viability. Deletion of both alleles of the CaRAS1 gene caused in vitro defects in morphological transition that were reversed 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. albicans cells in a macrophage cell culture assay and, in vivo, after infection of kidneys in a mouse model for systemic candidiasis. In the macrophage assay, the mutant cells were less resistant to phagocytosis. Moreover, the defects 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 pathway 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 medically relevant role for Ras in cellular morphogenesis and virulence in an important human infectious disease.
Leberer
E
E
Eukaryotic Genetics Group, Biotechnology Research Institute, National Research Council of Canada, 6100 Royalmount Avenue, Montreal, Quebec H4P 2R2, Canada. ekkehard.leberer@aventis.com
Harcus
D
D
Dignard
D
D
Johnson
L
L
Ushinsky
S
S
Thomas
D Y
DY
Schröppel
K
K
D000818:Animals; D002176:Candida albicans / Q000254:growth & development* / Q000472:pathogenicity*; D002177:Candidiasis / Q000382:microbiology / Q000503:physiopathology; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D005656:Fungal Proteins; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D020935:MAP Kinase Signaling System; D017737:Macrophages, Peritoneal / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009024:Morphogenesis; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D014774:Virulence; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D005656:Fungal Proteins; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins