Proline catabolism is key to facilitatingCandida albicanspathogenicity

Abstract

AbstractCandida albicans, the primary etiology of human mycoses, is well-adapted to catabolize proline to obtain energy to initiate morphological switching (yeast to hyphal) and for growth. We report thatput1-/-andput2-/- strains, carrying defectiveProlineUTilization genes, display remarkable proline sensitivity withput2-/- mutants being hypersensitive due to the accumulation of the toxic intermediate P5C, which inhibits mitochondrial respiration. Theput1-/- andput2-/-mutations attenuate virulence inDrosophilaand murine candidemia models. Using intravital 2-photon microscopy and label-free non-linear imaging, we visualized the initial stages ofC. albicanscells colonizing a kidney in real-time, directly deep in the tissue of a living mouse, and observed morphological switching of wildtype but not ofput2-/-cells. Multiple members of theCandidaspecies complex, includingC. auris, are capable of using proline as a sole energy source. Our results indicate that a tailored proline metabolic network tuned to the mammalian host environment is a key feature of opportunistic fungal pathogens.