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

Gifford, H.; Bedekovic, T.; Helmstetter, N.; Gregory, J.; Ma, Q.; Brand, A. C.; Wilson, D.; Rhodes, J.; Ramsdale, M.; Kudoh, T.; Farrer, R. A.

doi:10.1101/2024.10.22.619744

bioRxiv · 10.1101/2024.10.22.619744

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

Gifford, H.·Bedekovic, T.·Helmstetter, N.·Gregory, J.·Ma, Q.·Brand, A. C.·Wilson, D.·Rhodes, J.·Ramsdale, M.·Kudoh, T.·Farrer, R. A.

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Abstract

Candida auris is a critical priority fungal pathogen (World Health Organization). Clinical management is challenging due to a high mortality rate, rapidly increasing antifungal resistance, and frequent nosocomial outbreaks. A critical bottleneck in understanding virulence is the lack of gene expression profiling models during infection. We developed a fish embryo yolk-sac microinjection model using Aphanius dispar (Arabian killifish; AK) at human body temperature. This enabled interrogation of infection dynamics via dual host-pathogen RNA-seq across five major clades of C. auris (I-V). Host responses included heat shock, complement activation, and nutritional immunity, notably haem oxygenase (HMOX) expression during clade IV infection. We identified a pathogen transcriptional signature across all five clades of C. auris strongly enriched for putative xenosiderophore transmembrane transporters. We describe this novel family and a sub-clade of five putative haem transport-related (HTR) genes. Only the basal clade V isolate formed filaments, associated with canonical and atypical regulators of morphogenesis. Clades I and IV demonstrated increased virulence, accompanied by up-regulation of three HTR genes in clade IV, and the non-mating mating-type locus (MTL) gene PIKA in both clades. Our study provides new insight into C. auris pathogenesis, highlighting species-wide in vivo up-regulation of XTC genes during host tissue infection. Significance statementCandida auris is an emerging human fungal pathogen and global public health threat, yet in vivo transcriptomic analysis of tissue infection has remained elusive. Using yolk-sac infection in Arabian killifish, we profiled gene expression across five major C. auris clades. We found that the basal clade V uniquely undergoes filamentation during infection, while all clades upregulate members of a large, expanded family of xenosiderophore transporter candidate genes. These findings highlight the important roles for iron acquisition and morphological switching in pathogenesis, revealing potential mechanisms of immune evasion and fungal persistence, and identifying candidate targets for antifungal therapy.

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Gifford, H., Bedekovic, T., Helmstetter, N., Gregory, J., Ma, Q., Brand, A. C., Wilson, D., Rhodes, J., Ramsdale, M., Kudoh, T., Farrer, R. A.. 2024-10-23. Xenosiderophore transporter gene expression and clade-specific filamentation in Candida auris killifish infection. https://doi.org/10.1101/2024.10.22.619744

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