Tracing the evolutionary history and global expansion ofCandida aurisusing population genomic analyses

Abstract

<jats:title>Abstract</jats:title><jats:p><jats:italic>Candida auris</jats:italic> has 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, <jats:italic>C. auris</jats:italic> has been reported in over 30 additional countries. To trace this global emergence, we compared the genomes of 304 <jats:italic>C. auris</jats:italic> isolates 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. <jats:italic>C. auris</jats:italic> isolates 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 in <jats:italic>ERG11</jats:italic> as the most widespread mutation associated with azole resistance and S639P in <jats:italic>FKS1</jats:italic> for echinocandin resistance. Copy number variants in <jats:italic>ERG11</jats:italic> predominantly 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 in <jats:italic>C. auris</jats:italic>.</jats:p><jats:sec><jats:title>Importance</jats:title><jats:p>In less than a decade, <jats:italic>C. auris</jats:italic> has emerged in healthcare settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to other <jats:italic>Candida</jats:italic> species, <jats:italic>C. auris</jats:italic> is 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 new <jats:italic>C. auris</jats:italic> introductions. Through a global collaboration, we assessed genome evolution of isolates of <jats:italic>C. auris</jats:italic> from 19 countries. Here, we described estimated timing of the expansion of each <jats:italic>C. auris</jats:italic> clade 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.</jats:p></jats:sec>

Candida auris in an Australian health care facility: importance of screening high risk patients

“…Candida auris is an emerging, drug‐resistant yeast, responsible for hospital outbreaks internationally . First recognised as a new species of Candida in 2009, cases have been reported in over 30 countries, including the United Kingdom and United Arab Emirates . In outbreak settings, bloodstream, urinary tract and deep tissue infections have been reported, in addition to colonisation.…”

Nine Things Genomics Can Tell Us About Candida auris

“…C. auris has not been detected earlier than 2009 by The SENTRY Antifungal Surveillance Program, which has been collecting consecutive invasive Candida isolates from 135 participating medical centers in North America, Europe, Latin America and the Asia-Pacific regions since 1997 (Pfaller et al, 2019). However, molecular clock estimates from 304 worldwide genomes date the most recent common ancestor of each of the four clades within the last 339 years, and outbreak isolates from Clades I, III, and IV to 34-35 years ago (∼10 years prior to first being detected) (Chow et al, 2020). While the details of its origin remain unclear, C. auris is not the only fungal pathogen to have recently clinically emerged.…”

“…This isolate was taken from a patient in 2009 demonstrating independent emergences in 2009 of at least two of the C. auris lineages (Clade II and Clade III). A recent study comparing 204 genomes of C. auris using Bayesian molecular clock phylogenetics estimated the origin of each of the four clades within the last 339 years, and outbreak clusters (Clade I, III, and IV) originating 34-35 years ago (Chow et al, 2020), suggesting more historic samples were not identified.…”

“…Many of the described mutations can also be found in C. auris, but not all have the same effects (Muñoz et al, 2018). In both species, amino acid substitutions at F126L, Y132F, K143R result in azole resistance (Morio et al, 2010;Chowdhary et al, 2018;Healey et al, 2018), with Y132F the most widespread mutation associated with azole resistance (Chow et al, 2020). Another mechanism of azole resistance is the overexpression of Erg11p, which can be caused either by increasing the number of ERG11 transcription factors such as Upc2p or by duplicating ERG11 (Bhattacharya et al, 2019).…”

“…C. auris' resistance to echinocandins has been linked to mutations S639F, S639P and S639Y that occur in the highly conserved hot-spot 1 of FKS1 and decrease the sensitivity of the enzyme to the drug (Bidaud et al, 2018;Hou et al, 2019). S639P in FKS1 was recently shown to be the most widespread mutation associated with echinocandin resistance (Chow et al, 2020). A recent multi-omics analysis revealed that although the cell wall remodeling enzymes concentration was lower in C. auris when compared to C. albicans, in a drug-resistant C. auris isolate (MIC fluconazole: > 256 µg/mL, MIC caspofungin: 2 µg/mL) cell wall integrity proteins were upregulated, suggesting that the cell wall metabolism can be adjusted in response to drug treatment (Zamith-Miranda et al, 2019).…”