Role of squalene hopene cyclase in azole-resistance and virulence of Aspergillus fumigatus

As a major fungal pathogen, Aspergillus fumigatus can induce chronic, allergic or severe invasive infections, meanwhile its escalating resistance to azole antifungals has emerged as a global public health menace. Squalene, an essential molecule in the sterol biosynthesis pathway, can be cyclized by squalene hopene cyclase (SHC) to produce hopanoids and affect probably sterol biosynthesis modifying azole resistance; however, the physiological function of SHC in A. fumigatus pathogenesis is poorly understood. Overall design: Hereby it was found by genetic phylogenetic and protein structural analysis that the three shc genes in A. fumigatus demonstrate structural and functional diversification. Deletion of none of them substantially hindered fungal growth and development, but intriguingly, loss of shc1 gene increased the azole resistance of A. fumigatus whereas diminished its pathogenicity. Deletion of one of three shc genes could enhance the adhesion and invasion abilities of A. fumigatus towards lung epithelial cells. More, in A. fumigatus isolated from clinical samples the expression of shc1 gene was obviously higher in azole-resistant strains than in azole-susceptible strains, indicating a possible clinical significance of shc1 in relation to azole resistance. These findings demonstrated that SHC plays an important role in the regulation of azole-resistance and pathogenesis of A. fumigatus.