Proline catabolism is a key factor facilitating Candida albicans pathogenicity

by Fitz Gerald S. Silao, Tong Jiang, Biborka Bereczky-Veress, Andreas Kühbacher, Kicki Ryman, Nathalie Uwamohoro, Sabrina Jenull, Filomena Nogueira, Meliza Ward, Thomas Lion, Constantin F. Urban, Steffen Rupp, Karl Kuchler, Changbin Chen, Christiane Peuckert, Per O. Ljungdahl

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 Proline UTilization genes, display remarkable proline sensitivity with put2-/- mutants being hypersensitive due to the accumulation of the toxic intermediate pyrroline-5-carboxylate (P5C), which inhibits mitochondrial respiration. The put1-/- and put2-/- mutations attenuate virulence in Drosophila and murine candidemia models and decrease survival in human neutrophils and whole blood. Using intravital 2-photon microscopy and label-free non-linear imaging, we visualized the initial stages of C. albicans cells infecting 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.