Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.787422
Title: In-host adaptation of Aspergillus fumigatus : phenotypic and genotypic studies
Author: Ballard, Eloise
ISNI:       0000 0004 7972 5409
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2019
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Abstract:
In-host adaptation determines a microorganism's ability to survive in-host and successfully cause (chronic) infection. The in-host adaptation process of Aspergillus fumigatus, a fungal opportunistic pathogen, is poorly understood. The overall aim of this thesis was to advance our understanding of A. fumigatus in-host adaptation to both exogenous and endogenous stressors. This thesis characterised the in-host microevolution process of a series of 13 isogenic A. fumigatus isolates, obtained from a single chronic granulomatous disease patient suffering from persistent and recurrent invasive aspergillosis over 2 years. Throughout infection, these isolates acquired resistance to itraconazole, voriconazole and posaconazole. This resistance was attributed to both cyp51Adependent and -independent mechanisms. Differences in fungal growth and virulence were observed, as well as conidiation defects in isolates later recovered. Whole genome comparisons identified 248 non-synonymous single nucleotide polymorphisms. To gain further insight into the genetic in-host adaptation process, investigation into the phenotypic impact of specific in-host acquired single nucleotide polymorphisms was performed using sexual crossing, bulk segregant analysis and CRISPR-Cas9. Notably, a 167* single nucleotide polymorphism in an uncharacterised gene (AFUA_7G01960) was shown to confer enhanced itraconazole resistance and decreased ergosterol content. To gain further insight into the in-host adaptation process of A. fumigatus to endogenous stressors such as antimicrobial peptides, the anti-Aspergillus activity of specific antimicrobial peptides was characterised. Lysozyme and histones were identified to have antifungal activity against A. fumigatus hyphae, while histones, ß-defensin-1 and lactoferrin inhibited germination of A. fumigatus conidia. No evidence of in-host acquired resistance to these specific antimicrobial peptides was identified. In summary, we describe for the first time in depth the phenotypic and genotypic inhost adaptation process of A. fumigatus. We also characterised for the first time the anti-Aspergillus activity of specific antimicrobial peptides.
Supervisor: Warris, Adilia ; Brown, Alistair J. P. Sponsor: Biotechnology and Biological Sciences Research Council (BBSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.787422  DOI: Not available
Keywords: Aspergillus fumigatus ; Genomics ; Phenotype ; Azoles
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