Global Stress Responses Identify the Functionally Divergent Regulators Required for Candida auris Commensalism and Pathogenicity.

Given its global distribution and high transmissibility in the environment, Candida auris poses a serious threat to global public health. However, the underlying mechanisms of its adaptive strategies remain poorly understood. Here we delineate the pan-genome structures of 1,306 representative C. auris isolates collected from 28 countries. In addition to the clade-related genetic diversity and highly variable pan-genomes, we identify the key regulatory modules and genes specific to C. auris in response to 32 different host microenvironment-mimicking stresses. Through comparative analysis with evolutionarily close fungal relatives, we uncover both shared and species-specific transcriptional responses in C. auris. Intriguingly, our results reveal a distinct pathogenic role for the conserved iron regulon in this species. Unexpectedly, we also identify an evolutionarily divergent functional role for RIM101 in regulating both pathogenicity and commensalism of C. auris. Mechanistically, the high-affinity glucose transporters were found to enhance the tolerance to alkaline stress through alleviation of RIM101-dependent glucose repression in the host microenvironment. These findings provide mechanistic insights into the evolutionarily divergent adaptive strategies in both commensalism and virulence of the emerging critical priority fungal pathogen, C. auris.