Nutrient acquisition and metabolic adaptation in the context of Candida albicans virulence

Candida albicans is an opportunistic human fungal pathogen. Normally a harmless commensal and part of the microbiota of healthy humans, it can cause superficial to life-threatening systemic infections under distinct circumstances. Central for this switch is a variety of fungal pathogenicity mechanisms. Amongst them is a remarkable metabolic plasticity, which is intricately linked with other central fungal virulence traits like the yeast-to-hyphae switch. The chief aim of this thesis was to investigate three different aspects of these connections. The first part focused on nutrient acquisition on the example of proline – not only an especially valuable nutrient source for C. albicans but also a potent morphogenetic stimulus. In this study Gnp2 was identified as a specialized proline permease. Further analysis revealed an essential role for this permease for proline-induced morphogenesis and fungal resistance against macrophage killing and exposure to reactive oxygen species. In the second part a combinatorial approach of transcriptional and metabolic profiling was utilized to examine the metabolic adaptation of C. albicans to varying degrees of amino acid availability. Thereby, a repressive activity of the central amino acid metabolism regulator Stp2 was found on a metabolic gene cluster, which is required for the assimilation of hydroxybenzenes. Together with subsequent phenotypical analyses these findings suggested a so far unknown link between the metabolism of aromatic amino acids and hydroxybenzenes in C. albicans. Lastly, metabolic changes associated with the fungal switch from yeast to hyphal growth were investigated. A variety of morphotype-specific activities of metabolic pathways was identified, most notably including a stimulus-independent activation of the de novo sphingolipid biosynthesis in C. albicans hyphae. Further, by the pharmacological inhibition of this pathway its essential role for proper filamentation was verified.