Accelerated mutator phenotype in a clinical <i>Aspergillus fumigatus</i> isolate contributes to adaptive evolution.
The mutation frequency in clinical A. fumigatus isolates is about 15-times higher than in other strains, which may help the pathogen adapt to antifungal pressure.
Where it sits
this study against the rest of the 5-amino-1mq corpusSummary and findings
This study examined clinical isolates of Aspergillus fumigatus that showed irregular growth and rapid mutation accumulation during antifungal treatment. Whole-genome sequencing revealed a mutation frequency approximately 15-times higher than other strains. A mutation in the mre11 gene was identified as responsible for a 27% reduction in radial growth.
Abstract
The opportunistic pathogen <i>Aspergillus fumigatus</i> represents a major threat to immunocompromised individuals and is increasingly resistant to antifungal therapies. Resistance selection primarily takes place through environmental selection to azole fungicides, but in-host resistance may develop in patients with chronic aspergillosis receiving azole therapy. In this study, we examine clinical <i>A. fumigatus</i> isolates that exhibit irregular growth and accumulated mutations rapidly during antifungal treatment. Whole-genome sequencing of serial isolates revealed an accelerated mutation rate as the likely driver of the observed phenotype. The mutation frequency of this isolate was approximately 15-times higher than other <i>A. fumigatus</i> strains. We identified non-synonymous single nucleotide polymorphisms (SNPs) as potential loci involved in the increased mutation rate. Using CRISPR/Cas9 gene editing and comprehensive genomic analysis, we show that a mutation in <i>mre11</i>, a gene critical for genomic stability during DNA replication, is responsible for this elevated mutation rate. Mutations within <i>mre11</i> result in a 27% reduction in radial growth, highlighting the fitness cost associated with the higher mutation rate. All <i>mre11</i>-mutant isolates in this study belong to clade B, a lineage that rarely carries environmental azole-resistance mutations, potentially supporting in-host adaptation. The Phe332Leu allele was observed both in clinical and environmental isolates, suggesting that the mutator phenotype may represent a general adaptive strategy, allowing <i>A. fumigatus</i> to persist under prolonged azole pressure. We hypothesize that this heightened mutation background could facilitate the rapid spread of antifungal resistance alleles within <i>A. fumigatus</i> populations.
Background
The study addresses the adaptive evolution of Aspergillus fumigatus, particularly in immunocompromised individuals. Prior knowledge indicates that resistance to antifungal therapies is often selected through environmental pressures, but in-host resistance mechanisms are less understood. Understanding the mutation rates and mechanisms in clinical isolates is crucial for addressing the increasing threat posed by this pathogen.
Methods
The study utilized whole-genome sequencing of serial clinical isolates of A. fumigatus to assess mutation rates. The population included clinical isolates exhibiting irregular growth during antifungal treatment. The primary outcome measure was the mutation frequency, while secondary measures included the identification of specific mutations and their impact on growth.
Results
The primary finding was that the mutation frequency of the clinical isolate was approximately 15-times higher than that of other A. fumigatus strains. Additionally, mutations in the mre11 gene were linked to a 27% reduction in radial growth, indicating a fitness cost associated with the higher mutation rate.
Interpretation
This study's findings suggest a significant increase in mutation rates in clinical isolates of A. fumigatus, which may facilitate the rapid spread of antifungal resistance. While the statistical significance of the findings is clear, the clinical implications depend on the context of antifungal treatment and patient outcomes. Limitations include the focus on specific genetic mutations and the potential for confounding factors in clinical settings.
Key findings
- Mutation frequency was approximately 15-times higher than other A. fumigatus strains.
- Mutations within mre11 resulted in a 27% reduction in radial growth.
- All mre11-mutant isolates belonged to clade B, which rarely carries environmental azole-resistance mutations.
Limitations
- Not reported in abstract.