CsdA-LaeB Regulatory Hub Contributes to Aspergillus fumigatus Virulence via Fumiquinazoline C Biosynthesis

Fungal secondary metabolism plays a critical role in pathogen-host interactions, yet the regulatory networks linking metabolic reprogramming to virulence remain poorly understood. This study identifies a conserved regulatory hub in the human pathogen Aspergillus fumigatus, where the RNA-binding protein (RBP) CsdA interacts with the global regulator LaeB in the nucleus to control biosynthesis of the secondary metabolite fumiquinazoline C (FqC). Disruption of the CsdA-LaeB interaction hyperactivates FqC production, enhancing fungal colonization and lethality in murine invasive aspergillosis models. Integrative metabolomic and transcriptomic analyses reveal that CsdA and LaeB function as co-regulators of a broader secondary metabolic gene cluster network, with FqC emerging as an effector that mediates virulence in vivo. Genetic validation confirms that FqC is strictly required for the increased virulence phenotype of CsdA- or LaeB-deficient strains, while analyses of clinical isolates demonstrate a striking inverse correlation: reduced CsdA and LaeB expression coincides with elevated FqC production, showing consistency with the infection outcomes of the deletion mutants. This work identifies the RBP-based interaction that coordinates fungal metabolic virulence, shedding new light on the post-transcriptional regulatory logic linking secondary metabolism to pathogenicity and offering alternative strategies for diagnostic development and therapeutic intervention in invasive fungal diseases. Overall design: RNA-seq profile of wildtype CEA17 and their knockdown derivatives (csdA and laeB) at Day5 of metabolic differentiation.