Genomic Diversity of Azole-Resistant <named-content content-type="genus-species">Aspergillus fumigatus</named-content> in the United States

ABSTRACT Azole resistance in pathogenic Aspergillus fumigatus has become a global public health issue threatening the use of medical azoles. The environmentally occurring resistance mutations, TR34/L98H (TR34) and TR46/Y121F/T289A (TR46), are widespread across multiple continents and emerging in the...

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Autores principales:	Kizee A. Etienne, Elizabeth L. Berkow, Lalitha Gade, Natalie Nunnally, Shawn R. Lockhart, Karlyn Beer, I. King Jordan, Lavanya Rishishwar, Anastasia P. Litvintseva
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	azole resistance Aspergillus fumigatus whole-genome sequencing population genomics population structure TR34/L98H Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7245c76c23a141a8b12ae1a6e858b89b
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spelling	oai:doaj.org-article:7245c76c23a141a8b12ae1a6e858b89b2021-11-10T18:37:52ZGenomic Diversity of Azole-Resistant <named-content content-type="genus-species">Aspergillus fumigatus</named-content> in the United States10.1128/mBio.01803-212150-7511https://doaj.org/article/7245c76c23a141a8b12ae1a6e858b89b2021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01803-21https://doaj.org/toc/2150-7511ABSTRACT Azole resistance in pathogenic Aspergillus fumigatus has become a global public health issue threatening the use of medical azoles. The environmentally occurring resistance mutations, TR34/L98H (TR34) and TR46/Y121F/T289A (TR46), are widespread across multiple continents and emerging in the United States. We used whole-genome single nucleotide polymorphism (SNP) analysis on 179 nationally represented clinical and environmental A. fumigatus genomes from the United States along with 18 non-U.S. genomes to evaluate the genetic diversity and foundation of the emergence of azole resistance in the United States. We demonstrated the presence of clades of A. fumigatus isolates: clade A (17%) comprised a global collection of clinical and environmental azole-resistant strains, including all strains with the TR34/L98H allele from India, The Netherlands, the United Kingdom, and the United States, and clade B (83%) consisted of isolates without this marker mainly from the United States. The TR34/L98H polymorphism was shared among azole-resistant A. fumigatus strains from India, The Netherlands, the United Kingdom, and the United States, suggesting the common origin of this resistance mechanism. Six percent of azole-resistant A. fumigatus isolates from the United States with the TR34 resistance marker had a mixture of clade A and clade B alleles, suggestive of recombination. Additionally, the presence of equal proportions of both mating types further suggests the ongoing presence of recombination. This study demonstrates the genetic background for the emergence of azole resistance in the United States, supporting a single introduction and subsequent propagation, possibly through recombination of environmentally driven resistance mutations. IMPORTANCE Aspergillus fumigatus is one of the most common causes of invasive mold infections in patients with immune deficiencies and has also been reported in patients with severe influenza and severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2). Triazole drugs are the first line of therapy for this infection; however, their efficacy has been compromised by the emergence of azole resistance in A. fumigatus, which was proposed to be selected for by exposure to azole fungicides in the environment [P. E. Verweij, E. Snelders, G. H. J. Kema, E. Mellado, et al., Lancet Infect Dis 9:789–795, 2009, https://doi.org/10.1016/S1473-3099(09)70265-8]. Isolates with environmentally driven resistance mutations, TR34/L98H (TR34) and TR46/Y121F/T289A (TR46), have been reported worldwide. Here, we used genomic analysis of a large sample of resistant and susceptible A. fumigatus isolates to demonstrate a single introduction of TR34 in the United States and suggest its ability to spread into the susceptible population is through recombination between resistant and susceptible isolates.Kizee A. EtienneElizabeth L. BerkowLalitha GadeNatalie NunnallyShawn R. LockhartKarlyn BeerI. King JordanLavanya RishishwarAnastasia P. LitvintsevaAmerican Society for Microbiologyarticleazole resistanceAspergillus fumigatuswhole-genome sequencingpopulation genomicspopulation structureTR34/L98HMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	azole resistance Aspergillus fumigatus whole-genome sequencing population genomics population structure TR34/L98H Microbiology QR1-502
spellingShingle	azole resistance Aspergillus fumigatus whole-genome sequencing population genomics population structure TR34/L98H Microbiology QR1-502 Kizee A. Etienne Elizabeth L. Berkow Lalitha Gade Natalie Nunnally Shawn R. Lockhart Karlyn Beer I. King Jordan Lavanya Rishishwar Anastasia P. Litvintseva Genomic Diversity of Azole-Resistant <named-content content-type="genus-species">Aspergillus fumigatus</named-content> in the United States
description	ABSTRACT Azole resistance in pathogenic Aspergillus fumigatus has become a global public health issue threatening the use of medical azoles. The environmentally occurring resistance mutations, TR34/L98H (TR34) and TR46/Y121F/T289A (TR46), are widespread across multiple continents and emerging in the United States. We used whole-genome single nucleotide polymorphism (SNP) analysis on 179 nationally represented clinical and environmental A. fumigatus genomes from the United States along with 18 non-U.S. genomes to evaluate the genetic diversity and foundation of the emergence of azole resistance in the United States. We demonstrated the presence of clades of A. fumigatus isolates: clade A (17%) comprised a global collection of clinical and environmental azole-resistant strains, including all strains with the TR34/L98H allele from India, The Netherlands, the United Kingdom, and the United States, and clade B (83%) consisted of isolates without this marker mainly from the United States. The TR34/L98H polymorphism was shared among azole-resistant A. fumigatus strains from India, The Netherlands, the United Kingdom, and the United States, suggesting the common origin of this resistance mechanism. Six percent of azole-resistant A. fumigatus isolates from the United States with the TR34 resistance marker had a mixture of clade A and clade B alleles, suggestive of recombination. Additionally, the presence of equal proportions of both mating types further suggests the ongoing presence of recombination. This study demonstrates the genetic background for the emergence of azole resistance in the United States, supporting a single introduction and subsequent propagation, possibly through recombination of environmentally driven resistance mutations. IMPORTANCE Aspergillus fumigatus is one of the most common causes of invasive mold infections in patients with immune deficiencies and has also been reported in patients with severe influenza and severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2). Triazole drugs are the first line of therapy for this infection; however, their efficacy has been compromised by the emergence of azole resistance in A. fumigatus, which was proposed to be selected for by exposure to azole fungicides in the environment [P. E. Verweij, E. Snelders, G. H. J. Kema, E. Mellado, et al., Lancet Infect Dis 9:789–795, 2009, https://doi.org/10.1016/S1473-3099(09)70265-8]. Isolates with environmentally driven resistance mutations, TR34/L98H (TR34) and TR46/Y121F/T289A (TR46), have been reported worldwide. Here, we used genomic analysis of a large sample of resistant and susceptible A. fumigatus isolates to demonstrate a single introduction of TR34 in the United States and suggest its ability to spread into the susceptible population is through recombination between resistant and susceptible isolates.
format	article
author	Kizee A. Etienne Elizabeth L. Berkow Lalitha Gade Natalie Nunnally Shawn R. Lockhart Karlyn Beer I. King Jordan Lavanya Rishishwar Anastasia P. Litvintseva
author_facet	Kizee A. Etienne Elizabeth L. Berkow Lalitha Gade Natalie Nunnally Shawn R. Lockhart Karlyn Beer I. King Jordan Lavanya Rishishwar Anastasia P. Litvintseva
author_sort	Kizee A. Etienne
title	Genomic Diversity of Azole-Resistant <named-content content-type="genus-species">Aspergillus fumigatus</named-content> in the United States
title_short	Genomic Diversity of Azole-Resistant <named-content content-type="genus-species">Aspergillus fumigatus</named-content> in the United States
title_full	Genomic Diversity of Azole-Resistant <named-content content-type="genus-species">Aspergillus fumigatus</named-content> in the United States
title_fullStr	Genomic Diversity of Azole-Resistant <named-content content-type="genus-species">Aspergillus fumigatus</named-content> in the United States
title_full_unstemmed	Genomic Diversity of Azole-Resistant <named-content content-type="genus-species">Aspergillus fumigatus</named-content> in the United States
title_sort	genomic diversity of azole-resistant <named-content content-type="genus-species">aspergillus fumigatus</named-content> in the united states
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/7245c76c23a141a8b12ae1a6e858b89b
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Genomic Diversity of Azole-Resistant <named-content content-type="genus-species">Aspergillus fumigatus</named-content> in the United States

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