Azole-Resistance Development; How the Aspergillus fumigatus Lifecycle Defines the Potential for Adaptation

Abstract

In order to successfully infect or colonize human hosts or survive changing environments, Aspergillus fumigatus needs to adapt through genetic changes or phenotypic plasticity. The genomic changes are based on the capacity of the fungus to produce genetic variation, followed by selection of the genotypes that are most fit to the new environment. Much scientific work has focused on the metabolic plasticity, biofilm formation or the particular genetic changes themselves leading to adaptation, such as antifungal resistance in the host. Recent scientific work has shown advances made in understanding the natural relevance of parasex and how both the asexual and sexual reproduction can lead to tandem repeat elongation in the target gene of the azoles: the cyp51A gene. In this review, we will explain how the fungus can generate genetic variation that can lead to adaptation. We will discuss recent advances that have been made in the understanding of the lifecycle of A. fumigatus to explain the differences observed in speed and type of mutations that are generated under different environments and how this can facilitate adaptation, such as azole-resistance selection.

Spondylodiscitis Caused by Aspergillus Species

“…fumigatus is the most common and pathogenic species of Aspergilli. Resistance of A. fumigatus to antifungal agents, especially to azole compounds, represents a concern in the management of the disease [93,[96][97][98]. Even though an increased rate of azole resistance has been reported recently in the Netherlands and the United Kingdom, due to the extensive use of azoles as pesticides, the prevalence of azole resistance reportedly remains low in other countries [93].…”

Selection and Amplification of Fungicide Resistance in Aspergillus fumigatus in Relation to DMI Fungicide Use in Agronomic Settings: Hotspots versus Coldspots

“…Many triazoles and imidazoles are active against A. fumigatus [20,21], hence the introduction of medical triazole therapies to combat CPA and IA in the late 1980s [6,10]. Triazoles are currently the first-line choice of medical treatment for patients suffering from these conditions.…”

“…Strong evidence for the emergence of resistance within patients during DMI therapy has been provided by applying microsatellite typing to isolates recovered serially from infected individuals [10,11,30]. In-patient emergence of triazole resistance is probably associated with pulmonary cavities, within which the fungus can sporulate asexually from an aspergilloma, providing an opportunity for resistant variants to emerge that are then capable of being selected by the medical DMIs [6,11,12,23].…”

“…While there is some evidence for in-patient emergence of TRs [11,47,48] and nosocomial transfer (i.e., within the clinic) of ARAf isolates [49], the environment is likely to be a relevant source of IA patient contamination with resistant isolates [6]. Several studies have shown correspondence between specific ARAf genotypes isolated from patients and the general or their local environments [15,[50][51][52].…”

“…Aspergillus fumigatus is a ubiquitous saprophytic ascomycete fungus typically found in nature growing on decaying vegetation on and in soil [1][2][3]. It is thermotolerant, with a broad temperature range for growth (12-65 • C, optimum growth temperature of ~35 • C), and it benefits from high humidity (85-100%), characteristics that allow it to thrive in plant waste heaps [4][5][6].…”