Adaptation mechanisms of human fungal pathogens to long-term colonization in vivo are poorly understood. Moreover, how in vivo adaptation to the infection microenvironment affects disease outcomes is unknown. The ubiquitous environmental mold Aspergillus fumigatus causes a spectrum of disease in humans. In particular, patients with the genetic disorder Cystic Fibrosis (CF) have been associated with long-term fungal colonization. We are studying a series of clinical isolates obtained from a single CF patient over ~4.5 years. Genotypic and phenotypic analyses using this series of >50 A. fumigatus isolates has yielded several observations, including diverse colony and hyphal morphologies and stress resistance profiles. An interesting subset of 9 isolates, spanning ~1.5 years, display a unique “compact” colony morphology, inducible in the presence of glucose and preferred nitrogen sources in ambient oxygen. It is characterized by reduced radial growth, a dense colony of hyper-branching hyphae, and robust secretion of an extracellular matrix. Compact isolates also display increased tolerance to voriconazole and Congo Red, but poor oxidative and osmotic stress tolerance. Most strikingly, the compact isolates show an upwards of 55% increased radial growth in 1% oxygen. This finding suggests that the compact isolates have adapted to low oxygen conditions within the CF lung. We hypothesize that prolonged colonization of the CF lung results in adaptation and mutation in genes important for increased growth in low oxygen. To determine whether this phenomenon is specific to this series of isolates, analyses of isolates collected from other CF patients are ongoing. Current work is focused on identifying specific mutations that contribute to the increased growth using whole genome sequencing as well as classical and forward genetic approaches. This work will provide important knowledge to aid in diagnosis and treatment and will contribute to answering long-sought-after clinical questions related to isolation of fungal pathogens from colonized and infected tissue.
Full conference title:
- Fungal Genetics Conference 30th (2019)