Exploitation of the RNA interference pathway of the human fungal pathogen Aspergillus fumigatus

RNA-based therapeutics are an emerging class of drugs that are changing the way we treat infectious diseases. The versatility of this class is clearly on display in the rapid design and adaptation of the mRNA vaccines to SARS-CoV-2. Despite the success of these therapeutics against viruses, research into RNA-based therapeutics against human fungal pathogens, a major source of human morbidity and mortality, is lacking. Here, we provide proof-of-principle that RNA-based therapeutics hold potential against human fungal pathogens like Aspergillus fumigatus. We provide an improved mechanistic description of the RNA interference pathway of this important human pathogen by describing the genetic variation in RNAi-related genes using a large collection of environmental and clinical genomes, the proteins regulated by the system using advanced proteomics analysis, and the RNAi components essential for hairpin-induced silencing. We then exploit this pathway using a heterologously expressed hairpin RNA construct to silence the pabA gene of A. fumigatus to inhibit growth. The data presented here provide a foundation for a mechanistic description of novel RNA regulatory pathways in A. fumigatus and provide a first step towards the development of RNA-based therapeutics against this important human fungal pathogen.