Project description:Candida auris is an emerging infectious agent and WHO critical priority fungal pathogen. Rising pan-resistance, massive nosocomial outbreaks and diagnostic challenges complicate clinical treatment, with an associated human mortality rate of 45%. Importantly, in vivo gene expression of C. auris during infection has not been described to date. We developed the novel thermotolerant teleost fish embryo yolk-sac microinjection model of Aphanius dispar (Arabian Killifish, AK) for infection by each of the five major C. auris clades. This model enabled dual host-pathogen RNA-seq at 24 and 48 hours post injection (HPI) at mammalian temperature (37 °C), which has not been reported in other teleost fish models. Host gene expression indicated features of nutritional and innate immune responses, including haem-oxygenase and C-type lectin receptor expression. We identified an in vivo transcriptome signature common to all five clades of C. auris compared to in vitro expression that was highly enriched for putative xenosiderophore transmembrane transporters. We describe the seventeen-member xenosiderophore transport candidate family in terms of diverse in-host patterns of expression and cross-kingdom functional prediction. We discovered that only the basal clade V isolate formed filaments in vivo, corresponding with Candida-typical and atypical hypha-formation genetic signals, such as the novel adhesin SCF1. Furthermore, clades that were more virulent (I or IV vs II or III) were strongly characterised by upregulation of the majority of genes at the mating-type locus (MTL), including non-mating genes, consistent with a role for the MTL in C. auris pathogenicity. We hypothesise that both xenosiderophore transport genes and the MTL may play critical roles in C. auris virulence, and are urgent targets for potential therapy.
