In-host microevolution of Aspergillus fumigatus

a phenotypic and genotypic analysis

Eloise Ballard, Willem JG Melchers, Jan Zoll, Alistair J P Brown, Paul E Verweij, Adilia Warris (Corresponding Author)

Research output: Contribution to journalArticle

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Abstract

In order to survive, Aspergillus fumigatus must adapt to specific niche environments. Adaptation to the human host includes modifications facilitating persistent colonisation and the development of azole resistance. The aim of this study is to advance understanding of the genetic and physiological adaptation of A. fumigatus in patients during infection and treatment. Thirteen A. fumigatus strains were isolated from a single chronic granulomatous disease patient suffering from persistent and recurrent invasive aspergillosis over a period of 2 years. All strains had identical microsatellite genotypes and were considered isogenic. Whole genome comparisons identified 248 non-synonymous single nucleotide polymorphisms. These non-synonymous mutations have potential to play a role in in-host adaptation. The first 2 strains isolated were azole susceptible, whereas later isolates were itraconazole, voriconazole and/or posaconazole resistant. Growth assays in the presence and absence of various antifungal stressors highlighted minor changes in growth rate and stress resistance, with exception of one isolate showing a significant growth defect. Poor conidiation was observed in later isolates. In certain drug resistant isolates conidiation was restored in the presence of itraconazole. Differences in virulence were observed as demonstrated in a Galleria mellonella infection model. We conclude that the microevolution of A. fumigatus in this patient has driven the emergence of both Cyp51A-independent and Cyp51A-dependent, azole resistance mechanisms, and additional phenotypes that are likely to have promoted fungal persistence.
Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalFungal Genetics and Biology
Volume113
Early online date23 Feb 2018
DOIs
Publication statusPublished - Apr 2018

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Aspergillus fumigatus
Azoles
Itraconazole
Growth
Physiological Adaptation
Chronic Granulomatous Disease
Aspergillosis
Infection
Microsatellite Repeats
Single Nucleotide Polymorphism
Virulence
Genotype
Genome
Phenotype
Mutation
Pharmaceutical Preparations
Therapeutics

Keywords

  • aspergillus fumigatus
  • in-host microevolution
  • azole-resistance
  • fungal growth
  • whole genome sequencing

Cite this

Ballard, E., Melchers, W. JG., Zoll, J., Brown, A. J. P., Verweij, P. E., & Warris, A. (2018). In-host microevolution of Aspergillus fumigatus: a phenotypic and genotypic analysis. Fungal Genetics and Biology, 113, 1-13. https://doi.org/10.1016/j.fgb.2018.02.003

In-host microevolution of Aspergillus fumigatus : a phenotypic and genotypic analysis. / Ballard, Eloise; Melchers, Willem JG ; Zoll, Jan; Brown, Alistair J P; Verweij, Paul E; Warris, Adilia (Corresponding Author).

In: Fungal Genetics and Biology, Vol. 113, 04.2018, p. 1-13.

Research output: Contribution to journalArticle

Ballard, E, Melchers, WJG, Zoll, J, Brown, AJP, Verweij, PE & Warris, A 2018, 'In-host microevolution of Aspergillus fumigatus: a phenotypic and genotypic analysis', Fungal Genetics and Biology, vol. 113, pp. 1-13. https://doi.org/10.1016/j.fgb.2018.02.003
Ballard, Eloise ; Melchers, Willem JG ; Zoll, Jan ; Brown, Alistair J P ; Verweij, Paul E ; Warris, Adilia. / In-host microevolution of Aspergillus fumigatus : a phenotypic and genotypic analysis. In: Fungal Genetics and Biology. 2018 ; Vol. 113. pp. 1-13.
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N1 - Acknowledgments We are thankful to Kenny Ntwari Nindorera for performing the G. mellonella survival studies. EB, AB and AW are supported by the Wellcome Trust Strategic Award (grant 097377), the MRC Centre for Medical Mycology (grant MR/N006364/1) at the University of Aberdeen. AB was also supported by the Biotechnology and Biological Research Council (BB/K017365/1) and the Medical Research Council (MR/M026663/1). The work in this paper is funded by a BBSRC EASTBIO grant. The funders had no role in study design, data interpretation, or the decision to submit the work for publication.

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N2 - In order to survive, Aspergillus fumigatus must adapt to specific niche environments. Adaptation to the human host includes modifications facilitating persistent colonisation and the development of azole resistance. The aim of this study is to advance understanding of the genetic and physiological adaptation of A. fumigatus in patients during infection and treatment. Thirteen A. fumigatus strains were isolated from a single chronic granulomatous disease patient suffering from persistent and recurrent invasive aspergillosis over a period of 2 years. All strains had identical microsatellite genotypes and were considered isogenic. Whole genome comparisons identified 248 non-synonymous single nucleotide polymorphisms. These non-synonymous mutations have potential to play a role in in-host adaptation. The first 2 strains isolated were azole susceptible, whereas later isolates were itraconazole, voriconazole and/or posaconazole resistant. Growth assays in the presence and absence of various antifungal stressors highlighted minor changes in growth rate and stress resistance, with exception of one isolate showing a significant growth defect. Poor conidiation was observed in later isolates. In certain drug resistant isolates conidiation was restored in the presence of itraconazole. Differences in virulence were observed as demonstrated in a Galleria mellonella infection model. We conclude that the microevolution of A. fumigatus in this patient has driven the emergence of both Cyp51A-independent and Cyp51A-dependent, azole resistance mechanisms, and additional phenotypes that are likely to have promoted fungal persistence.

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