Tracing the evolutionary history and global expansion ofCandida aurisusing population genomic analyses
Authors: Chow Nancy A. , Muñoz José F. , Gade Lalitha , Berkow Elizabeth , Li Xiao , Welsh Rory M. , Forsberg Kaitlin , Lockhart Shawn R. , Adam Rodney , Alanio Alexandre , Alastruey-Izquierdo Ana , Althawadi Sahar , Belén Araúz Ana , Ben-Ami Ronen , Bharat Amrita , Calvo Belinda , Desnos-Ollivier Marie , Escandón Patricia , Gardam Dianne , Gunturu Revathi , Heath Christopher H. , Kurzai Oliver , Martin Ronny , Litvintseva Anastasia P. , Cuomo Christina A. 
Published: January 2020

Candida aurishas emerged globally as a multidrug-resistant yeast that can spread via nosocomial transmission. An initial phylogenetic study of isolates from Japan, India, Pakistan, South Africa, and Venezuela revealed four populations (Clades I, II, III, and IV) corresponding to these geographic regions. Since this description,C. aurishas been reported in over 30 additional countries. To trace this global emergence, we compared the genomes of 304C. aurisisolates from 19 countries on six continents. We found that four predominant clades persist across wide geographic locations. We observed phylogeographic mixing in most clades; Clade IV, with isolates mainly from South America, demonstrated the strongest phylogeographic substructure.C. aurisisolates from two clades with opposite mating types were detected contemporaneously in a single healthcare facility in Kenya. We estimated a Bayesian molecular clock phylogeny and dated the origin of each clade within the last 339 years; outbreak-causing clusters from Clades I, III, and IV originated 34-35 years ago. We observed high rates of antifungal resistance in Clade I, including four isolates resistant to all three major classes of antifungals. Mutations that contribute to resistance varied between the clades, with Y132F inERG11as the most widespread mutation associated with azole resistance and S639P inFKS1for echinocandin resistance. Copy number variants inERG11predominantly appeared in Clade III and were associated with fluconazole resistance. These results provide a global context for the phylogeography, population structure, and mechanisms associated with antifungal resistance inC. auris.

Importance

In less than a decade,C. aurishas emerged in healthcare settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to otherCandidaspecies,C. aurisis unique in its ability to spread via nosocomial transmission and its high rates of drug resistance. As part of the public health response, whole-genome sequencing has played a major role in characterizing transmission dynamics and detecting newC. aurisintroductions. Through a global collaboration, we assessed genome evolution of isolates ofC. aurisfrom 19 countries. Here, we described estimated timing of the expansion of eachC. aurisclade and of fluconazole resistance, characterized discrete phylogeographic population structure of each clade, and compared genome data to sensitivity measurements to describe how antifungal resistance mechanisms vary across the population. These efforts are critical for a sustained, robust public health response that effectively utilizes molecular epidemiology.