Proline catabolism is key to facilitating Candida albicans pathogenicity

Candida 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 that put1-/- and put2-/ - strains, carrying defective <underline>P</underline> roline <underline>UT</underline> ilization genes, display remarkable proline sensitivity with put2 -/- mutants being hypersensitive due to the accumulation of the toxic intermediate P5C, which inhibits mitochondrial respiration. The put1-/ - and put2-/- mutations attenuate virulence in Drosophila and murine candidemia models. Using intravital 2-photon microscopy and label-free non-linear imaging, we visualized the initial stages of C. albicans cells colonizing a kidney in real-time, directly deep in the tissue of a living mouse, and observed morphological switching of wildtype but not of put2-/- cells. Multiple members of the Candida species complex, including C. 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.