This study shows that nutrient availability controls Candida auris virulence and immune recognition, with glucose suppressing virulence and macrophage activation, while non-fermentable carbon sources trigger adhesion, filamentation, and stronger immune responses through nutrient-dependent transcriptional plasticity.
Candida auris recently emerged as human pathogen causing poorly treatable infections. Its transition from natural into host environments required modulation of mammalian immunity, but the mechanisms are poorly defined. Here we report that nutrient availability regulates the expression of virulence traits and immunomodulation by C. auris. In glucose C. auris represses its virulence traits and suppresses macrophage responses. Non-fermentable carbon sources activate two virulence traits, adhesion and filamentous morphogenesis, which are sensed by macrophages to activate the NLRP3 inflammasome and broad cytokine secretion. By phenotyping multiple clinical isolates, morphotypes and genetic mutants we defined carbon source-dependent transcriptional programs in C. auris and show that they are remarkably plastic. Plasticity is driven by nutrient-dependent titration of key transcriptional regulators, leading to phenotypic heterogeneity, distinct levels of filamentation and adhesion, and an immune response that is proportional to the magnitude of virulence trait expression. Our findings reveal that sensing of diverse nutrients in host environment allows C. auris to trade off activation of its virulence traits against recognition by host immunity.