Abstract
Certain Aspergillus fungi cause aspergillosis, a set of diseases that typically affect immunocompromised individuals. Most cases of aspergillosis are caused by Aspergillus fumigatus, which infects millions of people annually. Some closely related so-called cryptic species, such as Aspergillus lentulus, can also cause aspergillosis, albeit at lower frequencies, and they are also clinically relevant. Few antifungal drugs are currently available for treating aspergillosis and there is increasing worldwide concern about the presence of antifungal drug resistance in Aspergillus species. Furthermore, isolates from both A. fumigatus and other Aspergillus pathogens exhibit substantial heterogeneity in their antifungal drug resistance profiles. To gain insights into the evolution of antifungal drug resistance genes in Aspergillus, we investigated signatures of positive selection in 41 genes known to be involved in drug resistance across 42 susceptible and resistant isolates from 12 Aspergillus section Fumigati species. Using codon-based site models of sequence evolution, we identified ten genes that contain 43 sites with signatures of ancient positive selection across our set of species. None of the sites that have experienced positive selection overlap with sites previously reported to be involved in drug resistance. These results identify sites that likely experienced ancient positive selection in Aspergillus genes involved in resistance to antifungal drugs and suggest that historical selective pressures on these genes likely differ from any current selective pressures imposed by antifungal drugs.
Highlights
Aspergillus fumigatus is an important fungal pathogen that causes aspergillosis, a spectrum of diseases that includes aspergilloma, allergic bronchopulmonary aspergillosis, and invasive pulmonary aspergillosis (Latgé and Chamilos, 2019)
Our phylogeny is consistent with previous studies (Houbraken et al, 2020; Dos Santos et al, 2020a,b) that assigned isolates of species into four series: Fumigati (A. novofumigatus, A. fischeri, A. oerlinghausenensis, A. fumigatus, A. fumigatiaffinis, and A. lentulus), Unilateralis (A. turcosus and A. hiratsukae), Viridinutantes (A. udagawae, A. viridinutans, and A. felis), and Thermomutati (A. thermomutatus)
Sites previously reported to contribute to antifungal resistance did not overlap with sites under positive selection, suggesting that any current selective pressures imposed by antifungals may differ from historical signatures of selection on these genes
Summary
Aspergillus fumigatus is an important fungal pathogen that causes aspergillosis, a spectrum of diseases that includes aspergilloma, allergic bronchopulmonary aspergillosis, and invasive pulmonary aspergillosis (Latgé and Chamilos, 2019). A few other Aspergillus species, including closely related species that belong to section Fumigati, are known to be pathogenic (Steenwyk et al, 2019; Rokas et al, 2020). The first-line drugs against aspergillosis are the azoles, with echinocandins or amphotericin B as alternative or complementary treatments (Denning and Bromley, 2015; Novak et al, 2020) Azoles such as itraconazole, voriconazole, and posaconazole are fungicidal to Aspergillus spp. and target the ergosterol biosynthesis pathway by inhibiting lanosterol 14α-demethylase (cyp51A), resulting in accumulation of 14methylated sterols in the cell membrane. Echinocandins disrupt the tips of hyphal walls, increasing the internal osmotic pressure and causing cell death (Nishiyama et al, 2005; Enoch et al, 2014)
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