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Aneuploidy Is Associated with Azole Resistance in Aspergillus fumigatus
Aiah Khateb1,2,3, Sara Gago1, Michael Bromley1
1Manchester Fungal Infection Group, Division of Evolution Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Core Technology Facility, Manchester, United Kingdom.
Abstract:
Azole resistance in Aspergillus fumigatus is on the rise. Nontarget-mediated mechanisms are a common cause of azole resistance in chronic pulmonary aspergillosis (CPA). Here, we investigate resistance mechanisms using whole-genome sequencing. Sixteen azole-resistant A. fumigatus isolates from CPA were sequenced to assess genome rearrangements. Seven out of 16 CPA isolates showed genomic duplications compared to zero out of 18 invasive isolates. Duplication of regions, including cyp51A, increased gene expression. Our results suggest aneuploidy as an azole resistance mechanism in CPA.
Insights
Genomic duplications, including in the cyp51A gene, are linked to azole resistance in Aspergillus fumigatus from chronic pulmonary aspergillosis. Aneuploidy may be a key resistance mechanism.
Area of Science:
- Medical Mycology
- Genomics
- Antifungal Resistance
Background:
- Azole resistance in Aspergillus fumigatus is a growing clinical concern.
- Nontarget-mediated mechanisms frequently drive azole resistance in chronic pulmonary aspergillosis (CPA).
Purpose of the Study:
- To investigate genomic rearrangements as a mechanism of azole resistance in Aspergillus fumigatus.
- To assess the role of aneuploidy in azole resistance in CPA isolates.
Main Methods:
- Whole-genome sequencing of 16 azole-resistant Aspergillus fumigatus isolates from CPA patients.
- Comparative genomic analysis to identify genome rearrangements.
- Gene expression analysis of key resistance-associated genes.
Main Results:
- Seven out of 16 CPA isolates exhibited genomic duplications, unlike the 0/18 invasive isolates.
- Duplication of regions, notably including the cyp51A gene, was observed.
- Increased gene expression was associated with these duplications.
Conclusions:
- Genomic duplications and aneuploidy are identified as potential mechanisms of azole resistance in Aspergillus fumigatus.
- These findings highlight the importance of genomic instability in antifungal drug resistance.
- Further research into aneuploidy's role in CPA is warranted.
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