Thermal adaptation crosstalk with azole response through lncRNA in Aspergillus fumigatus

As Earths temperature rises, fungal pathogens are adapting, altering host-pathogen interactions, disease patterns, and response to the antimicrobial drugs. Here, we show that thermal adaptation to 42{degrees}C leads to reversible changes in fungal colony size, appearance, and azole drug response in the human pathogenic fungus Aspergillus fumigatus. Importantly, this adaptation is mediated by a lncRNA, afu-182, whose RNA levels negatively correlate with temperature. Growth at a lower temperature or ectopic upregulation of afu-182 RNA levels reverses the temperature adaptation. Global transcriptomic analyses show an enrichment of pathogenesis-associated genes at 37{degrees}C and 42{degrees}C compared to 25{degrees}C. Interestingly, we found that small heat shock proteins and chaperones, but not ATP-dependent heat-shock proteins, are negatively regulated by afu-182 at 37{degrees}C and 42{degrees}C at transcriptional level. Previously, we have shown that {Delta}afu-182 strains produce worse disease outcomes in a murine model of invasive pulmonary aspergillosis (IPA). Here, more importantly, we show that the overexpression of afu-182 in clinically azole-resistant isolates increased survival in a murine model of IPA. Taken together, fungal adaptation to increased temperature leads to a decrease in afu-182 RNA levels that is associated with worse disease outcomes upon azole treatment. This provides a framework to take temperature into account when analyzing the rise in azole MIC in environmental and clinical isolates. Significance statementAspergillus fumigatus is the causative agent of most mold associated infections and can tolerate temperatures above 50{degrees}C. A lncRNA levels negatively correlate with increasing temperature, and this increases the fungis ability to tolerate azole drugs both in vitro and in vivo. Changing the levels of afu-182 improves anti-fungal treatment outcomes.