Aspergillus fumigatus causes a range of diseases in humans, some of which are characterized by fungal persistence. A. fumigatus may persist by adapting to the human lung environment through physiological and genomic changes. The fungal strategy is to create genetic diversity by spontaneous mutations or recombination, and subsequent selection of genotypes most adapted to the new environment. Any stress factor can cause mutations to emerge that enable the fungus to overcome the stress factor and survive and reproduce in the new environment. Azole exposure is an example of a stress factor that causes mutations to emerge that render resistance. The mode of reproduction, i.e. sexual, parasexual, or asexual, is probably crucial for the adaptative potential of aspergillus. The various aspergillus diseases are characterized by different fungal morphotypes including hyphal growth or asexual reproduction. Little is known about the genomic dynamic of aspergilla in the human lung, but there are several clues that support fungal adaptation, especially in patients with chronic aspergillosis. As any change in the environment may provoke adaptation, switching between azoles in patients with chronic pulmonary aspergillosis (CPA) may result in a high-level pan-triazoleresistant phenotype through the accumulation of resistance mutations. Alternatively, when azole therapy is stopped, an azole-free environment is created that may prompt selection for compensatory mutations that overcome any fitness costs that are expected to accompany resistance development. As a consequence, starting, switching, and stopping azole therapy has the risk of selecting for highly resistant strains with wild-type fitness. As similar adaptation is expected to occur in response to other stress factors such as endogenous antimicrobial peptides, over time the fungus will become increasingly adapted to the lung environment thereby limiting the probability of eradication. In-host adaptation challenges current management strategies including switching between azole compounds in patients with CPA and tolerating colonization in patients with cystic fibrosis. Future research should include investigating the genomic dynamics during infection in order to understand the key factors facilitating adaptation of Aspergillus.
Full conference title:
- TIMM 8th (2017)