Journal
FUNGAL GENETICS AND BIOLOGY
Volume 113, Issue -, Pages 1-13Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.fgb.2018.02.003
Keywords
Aspergillus fumigatus; In-host microevolution; Azole-resistance; Fungal growth; Whole genome sequencing
Categories
Funding
- Wellcome Trust Strategic Award [097377]
- MRC Centre for Medical Mycology at the University of Aberdeen [MR/N006364/1]
- Biotechnology and Biological Research Council [BB/K017365/1]
- Medical Research Council [MR/M026663/1]
- BBSRC EASTBIO grant
- BBSRC [1654598, BB/K017365/1] Funding Source: UKRI
- MRC [MR/M026663/1, MR/N006364/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/K017365/1, 1654598] Funding Source: researchfish
- Medical Research Council [MR/M026663/1, MR/N006364/1] Funding Source: researchfish
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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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