ABSTRACT
The PKA pathway is a signaling pathway involved in virulence in Candida albicans. This mechanism can be activated via addition of glucose and activation involves at least two proteins, namely Cdc25 and Ras1. Both proteins are involved in specific virulence traits. However, it is not clear if Cdc25 and Ras1 also affect virulence independently of PKA. C. albicans holds a second, atypical, Ras protein, Ras2, but its function in PKA activation is still unclear. We investigated the role of Cdc25, Ras1, and Ras2 for different in vitro and ex vivo virulence characteristics. We show that deletion of CDC25 and RAS1 result in less toxicity towards oral epithelial cells, while deletion of RAS2 has no effect. However, toxicity towards cervical cells increases in both the ras2 and the cdc25 mutants while it decreases in a ras1 mutant compared to the WT. Toxicity assays using mutants of the transcription factors downstream of the PKA pathway (Efg1) or the MAPK pathway (Cph1) show that the ras1 mutant shows similar phenotypes as the efg1 mutant, whereas the ras2 mutant shows similar phenotypes as the cph1 mutant. These data show niche-specific roles for different upstream components in regulating virulence through both signal transduction pathways.
ABSTRACT
To treat infections caused by Candida albicans, azoles, polyenes, and echinocandins are used. However, resistance occurs against all three, so there is an urgent need for new antifungal drugs with a novel mode of action. Recently, it became clear that central metabolism plays an important role in the virulence of C. albicans. Glycolysis is, for example, upregulated during virulence conditions, whereas the glyoxylate cycle is important upon phagocytosis by host immune cells. These findings indicate that C. albicans adapts its metabolism to the environment for maximal virulence. In this review, we provide an overview of the potency of different central metabolic pathways and their key enzymes as potential antifungal drug targets.
