Long Terminal Repeat Retrotransposon Afut4 Promotes Azole Resistance of Aspergillus fumigatus by Enhancing the Expression of sac1 Gene

Aspergillus fumigatus causes a series of invasive diseases, including the high-mortality invasive aspergillosis, and has been a serious global health threat because of its increased resistance to the first-line clinical triazoles. We analyzed the whole-genome sequence of 15 A. fumigatus strains from China and found that long terminal repeat retrotransposons (LTR-RTs), including , and , are most common and have the largest total nucleotide length among all transposable elements in A. fumigatus. Deleting one of the most enriched in azole-resistant strains decreased azole resistance and downregulated its nearby gene, , but it did not significantly affect the expression of genes of the ergosterol synthesis pathway. We then discovered that of had promoter activity and enhanced the adjacent gene expression. We found that is important to A. fumigatus, and the upregulated caused elevated resistance of A. fumigatus to azoles. Finally, we showed that has an evolution pattern similar to that of the whole genome of azole-resistant strains due to azoles; phylogenetic analysis of both the whole genome and suggests that the insertion of might have preceded the emergence of azole-resistant strains. Taking these data together, we found that the LTR-RT might be involved in the regulation of azole resistance of A. fumigatus by upregulating its nearby gene.