Large-scale genome re-annotation uncovers pathogen-specific lncRNA regulators of fungal growth and virulence

Invasive fungal infections pose a serious global health threat. Although core cellular processes are broadly conserved across fungi, only a small fraction of known species cause severe human disease, suggesting that pathogenicity may depend in part on pathogen-specific regulators. However, such elements remain poorly understood because they often lack recognizable homologs, limiting accurate annotation and functional characterization. Here, using the invasive mold Aspergillus fumigatus as a model, we combined transcriptome-guided re-annotation with functional screening to identify previously unrecognized long non-coding RNAs (lncRNAs) required for fungal growth and virulence. Among 423 loci previously annotated as Fumigati section-specific protein-coding genes, 176 were reclassified as non-coding, revealing widespread annotation errors that had obscured potential regulators. We identified two lncRNAs, SSP7 and SSP8, that are required for hyphal growth and virulence in a murine infection model. Mechanistically, SSP7 binds the coding region of pprA mRNA, promotes its association with polysomes and translation, and thereby sustains mitochondrial function, whereas SSP8 contributes to amino acid homeostasis. Together, these findings demonstrate for the first time that pathogen-specific lncRNAs can fine-tune conserved cellular processes to generate distinct fungal growth and virulence traits, and reveal a novel translational regulatory mechanism in fungal pathogenicity.