Discovery of the Diploid Form of the Emerging Fungal Pathogen Candida auris

Abstract

The new multidrug-resistant pathogen Candida auris was first described in 2009 in Japan and has emerged in many countries worldwide. This human fungal pathogen has long been considered a haploid fungus. Here, we report the discovery of the diploid form and spontaneous ploidy shifts in clinical isolates of C. auris. Haploid and diploid cells of C. auris differ in several aspects including growth rates, virulence, and global gene expression profiles. For example, diploid cells exhibit a slower growth rate than haploid cells in in vitro culture media; however, they are more virulent than haploid cells in a mouse systemic infection model. Global transcriptional expression analysis demonstrates that both haploid and diploid cells express a set of ploidy-enriched genes, which are involved in the regulation of metabolism, cell wall maintenance, translation and DNA replication, and other important biological processes. Antifungal susceptibility testing shows that haploid and diploid cells exhibit similar responses when treated with a number of antifungals. Taken together, haploid and diploid cells may have different fitness responses to diverse niches, and ploidy changes could be an adaptive strategy of C. auris to environmental changes. Our findings shed new light on the biology and pathogenesis of this emerging fungal pathogen.

Adenylyl Cyclase and Protein Kinase A Play Redundant and Distinct Roles in Growth, Differentiation, Antifungal Drug Resistance, and Pathogenicity of Candida auris

“…Recently, it has been reported that C. auris in all clades can undergo a ploidy switch from haploid to diploid ( 54 ). Diploid cells grew more slowly but were larger and more virulent than the haploid cells ( 54 ).…”

“…Recently, it has been reported that C. auris in all clades can undergo a ploidy switch from haploid to diploid ( 54 ). Diploid cells grew more slowly but were larger and more virulent than the haploid cells ( 54 ). Considering the role of the cAMP/PKA pathway in morphological “switching” to pseudohyphae formation ( Fig.…”

“…We first measured the frequency of ploidy shifting in all strains by plating each strain on solid YPD medium containing phloxine B. In this situation, the colonies will appear white or pink, depending on whether they consist of haploid or diploid cells, respectively ( 54 ). A small percentage (approximately 0.2%) of WT cells converted to diploid after 5 to 7 days of incubation ( Fig.…”

“…Second, both C. auris cyr1 Δ and tpk1 Δ tpk2 Δ mutants not only had severely disrupted growth at 37°C, but also exhibited increased sensitivity to stress. It may be that the increased haploid-to-diploid switching frequency of the tpk1 Δ tpk2 Δ mutant contributes to the virulence of C. auris by compensating for its retarded cell growth; it has been shown that diploid C. auris cells are more virulent than haploid ones ( 54 ). It is unclear why the virulence of the bcy1 Δ mutant was attenuated.…”

A Markerless CRISPR-Mediated System for Genome Editing in Candida auris Reveals a Conserved Role for Cas5 in the Caspofungin Response

“…Since most C. auris clinical isolates are haploid and, thus, directly compatible with our LEUpOUT system, most C. auris isolates should be amenable to our genome editing system without requiring any prior strain engineering. One group has recently identified highly virulent diploid isolates of C. auris ( 29 ), which would require prior strain modification to be compatible with our genome editing system; however, we anticipate that the generation of LEU2 hemizygous strains using traditional gene deletion approaches should enable the use of our genome editing system in C. auris diploids, as has been demonstrated with a similar genome editing system in C. albicans ( 24 ).…”