A long non-coding RNA regulates triazole antifungal susceptibility and virulence in Aspergillus fumigatus

Azole-resistant Aspergillus infections are a source of increasing concern with limited alternative therapeutic options. However, as most infections are still caused by azole-susceptible Aspergillus strains, there is a need to better understand fungal responses to azole antifungals. To this end, we discover that a long non-coding RNA, afu-182, is a major regulator of cyp51-independent azole recalcitrant colony growth (ARC). We observe that loss of afu-182 leads to azole recalcitrant biofilms and poor treated disease outcomes in murine invasive pulmonary aspergillosis models. In contrast, overexpression of afu-182 significantly reduces fungal burden in animals treated with azole drugs. Whole transcriptome analyses revealed that azole drug treatment leads to an increase in transcripts of genes encoding 7-transmembrane domain proteins of the RTA1 family, and these proteins are negatively regulated by afu-182. Two RTA1 family genes downstream of afu-182 regulation have individual and combined effect in regulating fungal ARC. Taken together, our data show a trans-acting role of the long non-coding RNA afu-182 in regulating Aspergillus fumigatus response to azole drugs both in vitro and in vivo. These data provide further support for investigating antifungal drug responses beyond minimum inhibitory concentration testing.