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A long non-coding RNA, afu-182, regulates in vitro fungal azole response and virulence in Aspergillus fumigatus

ABSTRACT: Azole-resistant Aspergillus infections are a source of serious concern, as only three classes of drugs are available for treatment. However, as most infections are still caused by azole-sensitive AF strains, there is a need to better understand fungal response to azole drugs. Here, we have identified a long non-coding RNA, afu-182, as a major regulator of erg11-independent fungal azole recalcitrant colony growth (ARC), without an apparent change in azole’s minimum inhibitory concentration. As strains are currently classified in a binary system of resistant or susceptible to drugs, we show that afu-182 is a negative regulator of azole drug response, leading to azole recalcitrant biofilms and poor disease outcomes in an animal model upon azole treatment. Furthermore, overexpression of afu-182 significantly reduced fungal burden in animals treated with azole drugs, showing a genetic basis of action. Whole transcriptome analysis revealed that azole drugs lead to upregulation of 7-transmembrane domain proteins of the RTA1 family, and these proteins are negatively regulated by afu-182. Here, we characterized two RTA1 family genes downstream of afu-182 and showed their individual and additive effects in regulating fungal ARC. Taken together, our data show a trans-acting role of long non-coding RNA afu-182 in regulating fungal response to azole drugs both in vitro and in vivo. This provides a promising novel approach to determine the treatment outcomes, given that MIC alone is a poor predictor for treatment outcomes in infections caused by ASAF strains.

ORGANISM(S): Aspergillus fumigatus

PROVIDER: GSE309441 | GEO | 2026/02/26

REPOSITORIES: GEO

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