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Tracing the evolutionary history and global expansion of Candida auris using population genomic analyses
Open accessPreprint — published as 10.1128/mbio.03364-19 · Paper page
Abstract
Candida auris 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, C. auris has been reported in over 30 additional countries. To trace this global emergence, we compared the genomes of 304 C. auris 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. C. auris 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 ERG11 as the most widespread mutation associated with azole resistance and S639P in FKS1 for echinocandin resistance. Copy number variants in ERG11 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 C. auris . Importance: In less than a decade, C. auris has emerged in healthcare settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to other Candida species, C. auris 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 C. auris introductions. Through a global collaboration, we assessed genome evolution of isolates of C. auris from 19 countries. Here, we described estimated timing of the expansion of each C. auris 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.
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“Furthermore, C. auris clades display substantial genetic diversity and show distinct phenotypic traits, especially diminished susceptibilities to antifungal therapies (11–14).”
From Transcriptomics and Phenotyping Define Genetic Signatures Associated with Echinocandin Resistance in Candida auris (2022) · cites this paper as [13]
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“C. auris can show clinical resistance to all classes of antifungal drugs, including echinocandins that are usually recommended as first-line therapies for invasive candidiasis.”
From Transcriptomics and Phenotyping Define Genetic Signatures Associated with Echinocandin Resistance in Candida auris (2022) · cites this paper as [13]
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“This seems surprising as clade I as well as clade III isolates of C. auris display the lowest intraclade genetic diversities (13).”
From Transcriptomics and Phenotyping Define Genetic Signatures Associated with Echinocandin Resistance in Candida auris (2022) · cites this paper as [13]
In the citing paper
“C. auris isolates have been implicated in nosocomial outbreaks worldwide, with 5 distinct clades classified by region of independent emergence.”
From Clinical Efficacy and Safety of a Novel Antifungal, Fosmanogepix, in Patients with Candidemia Caused by Candida auris : Results from a Phase 2 Trial (2023) · cites this paper as [2]
In the citing paper
“Clade III isolates (found in South Africa) have also been detected in other countries, including Canada and the United States (2, 35).”
From Clinical Efficacy and Safety of a Novel Antifungal, Fosmanogepix, in Patients with Candidemia Caused by Candida auris : Results from a Phase 2 Trial (2023) · cites this paper as [2]
In the citing paper
“a notable proportion of C. auris clinical isolates have been observed to exhibit increased copy numbers of resistance-associated genes”
From Mutations in TAC1B : a Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris (2020) · cites this paper as [27]
In the citing paper
“Interrogation of a data set consisting of whole-genome sequencing data for 304 globally distributed C. auris isolates representing each of the four major clades revealed 14 nonsynonymous TAC1B mutations and one deletion”
From Mutations in TAC1B : a Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris (2020) · cites this paper as [27]
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Metadata
- Authors
- Chow, N. A., Muñoz, J. F., Gade, L., Berkow, E., Li, X., Welsh, R. M., Forsberg, K., Lockhart, S. R., Adam, R., Alanio, A., Alastruey-Izquierdo, A., Althawadi, S., Belén Araúz, A., Ben-Ami, R., Bharat, A., Calvo, B., Desnos-Ollivier, M., Escandón, P., Gardam, D., Gunturu, R., Heath, C. H., Kurzai, O., Martin, R., Litvintseva, A. P., & Cuomo, C. A.
- Affiliations
- Centers for Disease Control and Prevention (US)
- Broad Institute (US)
- Aga Khan University Hospital Nairobi (KE)
- Centre National de la Recherche Scientifique (FR)
- King Faisal Specialist Hospital & Research Centre (SA)
- Public Health Agency of Canada (CA)
- Universidad del Zulia (VE)
- Instituto Nacional de Salud (CO)
- Fiona Stanley Hospital (AU)
- The University of Western Australia (AU)
- University of Würzburg (DE)
- Corresponding author
- Litvintseva, Anastasia P.
- Cuomo, Christina A.
- ORCID
- Chow, Nancy A.
- Muñoz, José F.
- Gade, Lalitha
- Berkow, Elizabeth
- Welsh, Rory M.
- Forsberg, Kaitlin
- Lockhart, Shawn R.
- Adam, Rodney
- Alanio, Alexandre
- Alastruey-Izquierdo, Ana
- Althawadi, Sahar
- Bharat, Amrita
- Escandón, Patricia
- Gardam, Dianne
- Heath, Christopher H.
- Kurzai, Oliver
- Martin, Ronny
- Litvintseva, Anastasia P.
- Cuomo, Christina A.
- Venue
- mBio
- Publisher
- openRxiv
- Published
- 2020-01-07
- Volume
- 11
- Issue
- 2
- Pages
- e03364-19
- ISSN
- 2150-7511 (ISSN-L)
- PMC
- PMC7188998
- OpenAlex
- W3020256411
- Cited by
- 463
- References
- 57
- Citations by year
- 2026: 76 · 2025: 86 · 2024: 81 · 2023: 80 · 2022: 64 · 2021: 52 · 2020: 24
- FWCI
- 7.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion)
- UWA Profiles and Research Repository (UWA) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- eCommons - AKU (Aga Khan University) (submittedVersion)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Greater South Information System
- Funders
- U.S. Department of Health and Human Services (U19-AI110818)
- Canadian Institute for Advanced Research
- Broad Institute (U19AI110818)
- National Institutes of Health
- Centers for Disease Control and Prevention (U19AI110818)
- National Institute of Allergy and Infectious Diseases (U19AI110818)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Immunology and Microbiology › Microbiology › Yeasts and Rust Fungi Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Candida auris, evolutionary history, international expansion, phylogeography, fluconazole resistance, antifungal resistance, nosocomial transmission, invasive candidiasis, molecular epidemiology, population structure, whole genome sequencing
- MeSH terms
- Whole Genome Sequencing, Antifungal Agents, Azoles, Candida, Biological Evolution, Genes, Fungal, Genetics, Population, Humans, Mutation, Phylogeny, Fluconazole, Genome, Fungal, Molecular Epidemiology, Drug Resistance, Fungal, Echinocandins, Metagenomics, Candidiasis, Invasive, Phylogeography
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