Nonrandom Distribution of Azole Resistance across the Global Population of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

ABSTRACT The emergence of azole resistance in the pathogenic fungus Aspergillus fumigatus has continued to increase, with the dominant resistance mechanisms, consisting of a 34-nucleotide tandem repeat (TR34)/L98H and TR46/Y121F/T289A, now showing a structured global distribution. Using hierarchical...

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Autores principales:	Thomas R. Sewell, Jianing Zhu, Johanna Rhodes, Ferry Hagen, Jacques F. Meis, Matthew C. Fisher, Thibaut Jombart
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Aspergillus fumigatus antifungal chemicals azole resistance fungal pathogen fungicides global distribution Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2f216b8589974e92a6a9ff8cca0f59d4
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spelling	oai:doaj.org-article:2f216b8589974e92a6a9ff8cca0f59d42021-11-15T15:55:24ZNonrandom Distribution of Azole Resistance across the Global Population of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>10.1128/mBio.00392-192150-7511https://doaj.org/article/2f216b8589974e92a6a9ff8cca0f59d42019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00392-19https://doaj.org/toc/2150-7511ABSTRACT The emergence of azole resistance in the pathogenic fungus Aspergillus fumigatus has continued to increase, with the dominant resistance mechanisms, consisting of a 34-nucleotide tandem repeat (TR34)/L98H and TR46/Y121F/T289A, now showing a structured global distribution. Using hierarchical clustering and multivariate analysis of 4,049 A. fumigatus isolates collected worldwide and genotyped at nine microsatellite loci using analysis of short tandem repeats of A. fumigatus (STRAf), we show that A. fumigatus can be subdivided into two broad clades and that cyp51A alleles TR34/L98H and TR46/Y121F/T289A are unevenly distributed across these two populations. Diversity indices show that azole-resistant isolates are genetically depauperate compared to their wild-type counterparts, compatible with selective sweeps accompanying the selection of beneficial mutations. Strikingly, we found that azole-resistant clones with identical microsatellite profiles were globally distributed and sourced from both clinical and environmental locations, confirming that azole resistance is an international public health concern. Our work provides a framework for the analysis of A. fumigatus isolates based on their microsatellite profile, which we have incorporated into a freely available, user-friendly R Shiny application (AfumID) that provides clinicians and researchers with a method for the fast, automated characterization of A. fumigatus genetic relatedness. Our study highlights the effect that azole drug resistance is having on the genetic diversity of A. fumigatus and emphasizes its global importance upon this medically important pathogenic fungus. IMPORTANCE Azole drug resistance in the human-pathogenic fungus Aspergillus fumigatus continues to emerge, potentially leading to untreatable aspergillosis in immunosuppressed hosts. Two dominant, environmentally associated resistance mechanisms, which are thought to have evolved through selection by the agricultural application of azole fungicides, are now distributed globally. Understanding the effect that azole resistance is having on the genetic diversity and global population of A. fumigatus will help mitigate drug-resistant aspergillosis and maintain the azole class of fungicides for future use in both medicine and crop protection.Thomas R. SewellJianing ZhuJohanna RhodesFerry HagenJacques F. MeisMatthew C. FisherThibaut JombartAmerican Society for MicrobiologyarticleAspergillus fumigatusantifungal chemicalsazole resistancefungal pathogenfungicidesglobal distributionMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus fumigatus antifungal chemicals azole resistance fungal pathogen fungicides global distribution Microbiology QR1-502
spellingShingle	Aspergillus fumigatus antifungal chemicals azole resistance fungal pathogen fungicides global distribution Microbiology QR1-502 Thomas R. Sewell Jianing Zhu Johanna Rhodes Ferry Hagen Jacques F. Meis Matthew C. Fisher Thibaut Jombart Nonrandom Distribution of Azole Resistance across the Global Population of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
description	ABSTRACT The emergence of azole resistance in the pathogenic fungus Aspergillus fumigatus has continued to increase, with the dominant resistance mechanisms, consisting of a 34-nucleotide tandem repeat (TR34)/L98H and TR46/Y121F/T289A, now showing a structured global distribution. Using hierarchical clustering and multivariate analysis of 4,049 A. fumigatus isolates collected worldwide and genotyped at nine microsatellite loci using analysis of short tandem repeats of A. fumigatus (STRAf), we show that A. fumigatus can be subdivided into two broad clades and that cyp51A alleles TR34/L98H and TR46/Y121F/T289A are unevenly distributed across these two populations. Diversity indices show that azole-resistant isolates are genetically depauperate compared to their wild-type counterparts, compatible with selective sweeps accompanying the selection of beneficial mutations. Strikingly, we found that azole-resistant clones with identical microsatellite profiles were globally distributed and sourced from both clinical and environmental locations, confirming that azole resistance is an international public health concern. Our work provides a framework for the analysis of A. fumigatus isolates based on their microsatellite profile, which we have incorporated into a freely available, user-friendly R Shiny application (AfumID) that provides clinicians and researchers with a method for the fast, automated characterization of A. fumigatus genetic relatedness. Our study highlights the effect that azole drug resistance is having on the genetic diversity of A. fumigatus and emphasizes its global importance upon this medically important pathogenic fungus. IMPORTANCE Azole drug resistance in the human-pathogenic fungus Aspergillus fumigatus continues to emerge, potentially leading to untreatable aspergillosis in immunosuppressed hosts. Two dominant, environmentally associated resistance mechanisms, which are thought to have evolved through selection by the agricultural application of azole fungicides, are now distributed globally. Understanding the effect that azole resistance is having on the genetic diversity and global population of A. fumigatus will help mitigate drug-resistant aspergillosis and maintain the azole class of fungicides for future use in both medicine and crop protection.
format	article
author	Thomas R. Sewell Jianing Zhu Johanna Rhodes Ferry Hagen Jacques F. Meis Matthew C. Fisher Thibaut Jombart
author_facet	Thomas R. Sewell Jianing Zhu Johanna Rhodes Ferry Hagen Jacques F. Meis Matthew C. Fisher Thibaut Jombart
author_sort	Thomas R. Sewell
title	Nonrandom Distribution of Azole Resistance across the Global Population of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_short	Nonrandom Distribution of Azole Resistance across the Global Population of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full	Nonrandom Distribution of Azole Resistance across the Global Population of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_fullStr	Nonrandom Distribution of Azole Resistance across the Global Population of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full_unstemmed	Nonrandom Distribution of Azole Resistance across the Global Population of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_sort	nonrandom distribution of azole resistance across the global population of <named-content content-type="genus-species">aspergillus fumigatus</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/2f216b8589974e92a6a9ff8cca0f59d4
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Nonrandom Distribution of Azole Resistance across the Global Population of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

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