“Reassessing the Origins of Pathogenicity Incandida Aurisand Relatives Through Phylogenomic Analysis”

ABSTRACT Emerging fungal pathogens commonly originate from benign or non-pathogenic strains living in the natural environment. Assessing the evolutionary relationships between pathogenic and non-pathogenic species is one approach for tracing the origins of pathogenicity across species. The recently emerged human pathogen, Candida auris belongs to the Candida/Clavispora clade, a diverse group of 45 yeast species including human pathogens and environmental saprobes. C. auris is believed to have originated in the environment and recently transitioned to a human pathogen. We present a phylogenomic analysis of this clade aimed at testing for patterns implicated in the emergence of pathogenicity using an expanded sample of non-pathogenic strains and species. To build a robust framework for investigating these relationships, we developed a whole-genome sequence dataset of 108 isolates representing 18 species, including 4 newly sequenced species and 18 environmentally isolated strains. Our phylogeny, based on 619 orthologous genes, shows environmentally isolated species and strains interspersed with clinically isolated counterparts, rejecting the hypothesis of a single origin of pathogenicity within the lineage containing C. auris and its closest relatives. Our findings highlight the breadth of environments these yeasts inhabit, and imply, concerningly, that known pathogens could just as easily live outside the human body in diverse natural environments. Based on this result, we suggest that surveillance aimed at detecting emerging pathogens should expand to related environmentally-derived fungi with pathogenic potential. AUTHOR SUMMARY The rapid rise in the number of fungal pathogens over the past few decades has been linked to climate change, globalization, intensive farming practices, and an increase in immunocompromised individuals. Candida auris is an example of a recently emerged fungal pathogen capable of causing severe disease and large outbreaks in vulnerable patient populations. The evolutionary origins of C. auris are poorly understood, however, they are essential to understanding how and when this pathogen emerged. In this study, we investigated relationships between a sample of pathogenic and non-pathogenic strains and species in the Candida/Clavispora clade, a group of 45 yeast species including human pathogens (including C. auris ) and environmental saprobes. We used these relationships to test for patterns that might support differing pathogen emergence hypotheses. We found that the relationships between pathogens and non-pathogens suggest many transitions between humans and other environments, rather than a single origin of pathogenicity. It seems plausible that these pathogens, often found in harsh environmental conditions such as seawater, already possessed traits that make them suitable human pathogens, which are perpetuated by increased at-risk patient populations. We should, therefore, be vigilant in our surveillance for clinical isolation of yeasts belonging to this clade from humans.