Xenosiderophore transporter gene expression and clade-specific filamentation in Candida auris killifish infection

Candida auris is an emerging infectious agent and World Health Organisation (WHO) critical priority fungal pathogen. Rising drug resistance, massive nosocomial outbreaks and diagnostic challenges complicate clinical treatment, resulting in a patient mortality rate of ∼45%. Surprisingly, gene expression profiles of C. auris have not yet been described during infection in vivo . To understand transcriptional responses during in-host infection, we developed a thermo-relevant fish embryo yolk-sac microinjection model ( Aphanius dispar ; Arabian killifish; AK) that mimics human body temperature. This allowed us to interrogate infection dynamics through dual host-pathogen RNA-seq at 24 and 48 h post injection (HPI) at 37 °C across the five major clades (I-V) of C. auris . Host gene expression following infection indicated features of heat shock, complement activation, and nutritional immunity, including haem oxygenase ( HMOX ) expression in response to clade IV infection. We identified an in vivo transcriptional signature across five clades of C. auris that was highly enriched for putative xenosiderophore transmembrane transporters. We describe this newly-discovered seventeen-member xenosiderophore transporter candidate ( XTC ) family in terms of individual gene expression patterns, and a sub-clade of five putative haem transport-related ( HTR ) genes, also up-regulated during infection. Only the basal clade V isolate formed filaments during infection, coinciding with typical and atypical regulators of morphogenesis, including UME6 , HGC1 , and the novel adhesin SCF1 . Clades I and IV demonstrated increased virulence, coinciding with up-regulation of three HTR genes in clade IV, and the mating-type locus ( MTL ) non-mating gene PIKA in both. Our study suggests that XTC and HTR genes may play a critical role in C. auris virulence, making excellent targets for further investigation and potential therapy.