Genomic Context of Azole Resistance Mutations in <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Determined Using Whole-Genome Sequencing

ABSTRACT A rapid and global emergence of azole resistance has been observed in the pathogenic fungus Aspergillus fumigatus over the past decade. The dominant resistance mechanism appears to be of environmental origin and involves mutations in the cyp51A gene, which encodes a protein targeted by tria...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Alireza Abdolrasouli, Johanna Rhodes, Mathew A. Beale, Ferry Hagen, Thomas R. Rogers, Anuradha Chowdhary, Jacques F. Meis, Darius Armstrong-James, Matthew C. Fisher
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bfdb00b29b6c4126b66e655c3581f1ba
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:bfdb00b29b6c4126b66e655c3581f1ba
record_format	dspace
spelling	oai:doaj.org-article:bfdb00b29b6c4126b66e655c3581f1ba2021-11-15T15:49:02ZGenomic Context of Azole Resistance Mutations in <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Determined Using Whole-Genome Sequencing10.1128/mBio.00536-152150-7511https://doaj.org/article/bfdb00b29b6c4126b66e655c3581f1ba2015-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00536-15https://doaj.org/toc/2150-7511ABSTRACT A rapid and global emergence of azole resistance has been observed in the pathogenic fungus Aspergillus fumigatus over the past decade. The dominant resistance mechanism appears to be of environmental origin and involves mutations in the cyp51A gene, which encodes a protein targeted by triazole antifungal drugs. Whole-genome sequencing (WGS) was performed for high-resolution single-nucleotide polymorphism (SNP) analysis of 24 A. fumigatus isolates, including azole-resistant and susceptible clinical and environmental strains obtained from India, the Netherlands, and the United Kingdom, in order to assess the utility of WGS for characterizing the alleles causing resistance. WGS analysis confirmed that TR34/L98H (a mutation comprising a tandem repeat [TR] of 34 bases in the promoter of the cyp51A gene and a leucine-to-histidine change at codon 98) is the sole mechanism of azole resistance among the isolates tested in this panel of isolates. We used population genomic analysis and showed that A. fumigatus was panmictic, with as much genetic diversity found within a country as is found between continents. A striking exception to this was shown in India, where isolates are highly related despite being isolated from both clinical and environmental sources across >1,000 km; this broad occurrence suggests a recent selective sweep of a highly fit genotype that is associated with the TR34/L98H allele. We found that these sequenced isolates are all recombining, showing that azole-resistant alleles are segregating into diverse genetic backgrounds. Our analysis delineates the fundamental population genetic parameters that are needed to enable the use of genome-wide association studies to identify the contribution of SNP diversity to the generation and spread of azole resistance in this medically important fungus. IMPORTANCE Resistance to azoles in the ubiquitous ascomycete fungus A. fumigatus was first reported from clinical isolates collected in the United States during the late 1980s. Over the last decade, an increasing number of A. fumigatus isolates from the clinic and from nature have been found to show resistance to azoles, suggesting that resistance is emerging through selection by the widespread usage of agricultural azole antifungal compounds. Aspergillosis is an emerging clinical problem, with high rates of treatment failures necessitating the development of new techniques for surveillance and for determining the genome-wide basis of azole resistance in A. fumigatus.Alireza AbdolrasouliJohanna RhodesMathew A. BealeFerry HagenThomas R. RogersAnuradha ChowdharyJacques F. MeisDarius Armstrong-JamesMatthew C. FisherAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 3 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Alireza Abdolrasouli Johanna Rhodes Mathew A. Beale Ferry Hagen Thomas R. Rogers Anuradha Chowdhary Jacques F. Meis Darius Armstrong-James Matthew C. Fisher Genomic Context of Azole Resistance Mutations in <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Determined Using Whole-Genome Sequencing
description	ABSTRACT A rapid and global emergence of azole resistance has been observed in the pathogenic fungus Aspergillus fumigatus over the past decade. The dominant resistance mechanism appears to be of environmental origin and involves mutations in the cyp51A gene, which encodes a protein targeted by triazole antifungal drugs. Whole-genome sequencing (WGS) was performed for high-resolution single-nucleotide polymorphism (SNP) analysis of 24 A. fumigatus isolates, including azole-resistant and susceptible clinical and environmental strains obtained from India, the Netherlands, and the United Kingdom, in order to assess the utility of WGS for characterizing the alleles causing resistance. WGS analysis confirmed that TR34/L98H (a mutation comprising a tandem repeat [TR] of 34 bases in the promoter of the cyp51A gene and a leucine-to-histidine change at codon 98) is the sole mechanism of azole resistance among the isolates tested in this panel of isolates. We used population genomic analysis and showed that A. fumigatus was panmictic, with as much genetic diversity found within a country as is found between continents. A striking exception to this was shown in India, where isolates are highly related despite being isolated from both clinical and environmental sources across >1,000 km; this broad occurrence suggests a recent selective sweep of a highly fit genotype that is associated with the TR34/L98H allele. We found that these sequenced isolates are all recombining, showing that azole-resistant alleles are segregating into diverse genetic backgrounds. Our analysis delineates the fundamental population genetic parameters that are needed to enable the use of genome-wide association studies to identify the contribution of SNP diversity to the generation and spread of azole resistance in this medically important fungus. IMPORTANCE Resistance to azoles in the ubiquitous ascomycete fungus A. fumigatus was first reported from clinical isolates collected in the United States during the late 1980s. Over the last decade, an increasing number of A. fumigatus isolates from the clinic and from nature have been found to show resistance to azoles, suggesting that resistance is emerging through selection by the widespread usage of agricultural azole antifungal compounds. Aspergillosis is an emerging clinical problem, with high rates of treatment failures necessitating the development of new techniques for surveillance and for determining the genome-wide basis of azole resistance in A. fumigatus.
format	article
author	Alireza Abdolrasouli Johanna Rhodes Mathew A. Beale Ferry Hagen Thomas R. Rogers Anuradha Chowdhary Jacques F. Meis Darius Armstrong-James Matthew C. Fisher
author_facet	Alireza Abdolrasouli Johanna Rhodes Mathew A. Beale Ferry Hagen Thomas R. Rogers Anuradha Chowdhary Jacques F. Meis Darius Armstrong-James Matthew C. Fisher
author_sort	Alireza Abdolrasouli
title	Genomic Context of Azole Resistance Mutations in <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Determined Using Whole-Genome Sequencing
title_short	Genomic Context of Azole Resistance Mutations in <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Determined Using Whole-Genome Sequencing
title_full	Genomic Context of Azole Resistance Mutations in <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Determined Using Whole-Genome Sequencing
title_fullStr	Genomic Context of Azole Resistance Mutations in <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Determined Using Whole-Genome Sequencing
title_full_unstemmed	Genomic Context of Azole Resistance Mutations in <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Determined Using Whole-Genome Sequencing
title_sort	genomic context of azole resistance mutations in <named-content content-type="genus-species">aspergillus fumigatus</named-content> determined using whole-genome sequencing
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/bfdb00b29b6c4126b66e655c3581f1ba
work_keys_str_mv	AT alirezaabdolrasouli genomiccontextofazoleresistancemutationsinnamedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontentdeterminedusingwholegenomesequencing AT johannarhodes genomiccontextofazoleresistancemutationsinnamedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontentdeterminedusingwholegenomesequencing AT mathewabeale genomiccontextofazoleresistancemutationsinnamedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontentdeterminedusingwholegenomesequencing AT ferryhagen genomiccontextofazoleresistancemutationsinnamedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontentdeterminedusingwholegenomesequencing AT thomasrrogers genomiccontextofazoleresistancemutationsinnamedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontentdeterminedusingwholegenomesequencing AT anuradhachowdhary genomiccontextofazoleresistancemutationsinnamedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontentdeterminedusingwholegenomesequencing AT jacquesfmeis genomiccontextofazoleresistancemutationsinnamedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontentdeterminedusingwholegenomesequencing AT dariusarmstrongjames genomiccontextofazoleresistancemutationsinnamedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontentdeterminedusingwholegenomesequencing AT matthewcfisher genomiccontextofazoleresistancemutationsinnamedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontentdeterminedusingwholegenomesequencing
_version_	1718427546445414400

Genomic Context of Azole Resistance Mutations in <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Determined Using Whole-Genome Sequencing

Ejemplares similares