Elucidating the role of extracellular RNA in the innate immune defense against human fungal pathogens

Aspergillus fumigatus is an opportunistic fungal pathogen classified as a critical priority to global health by the WHO. Invasive pulmonary aspergillosis is associated with mortality rates of 30-85% in >2 million patients each year, with neutropenia the major risk factor for these severe infections. Thus, a refined definition of the antifungal neutrophil response is likely key to improved therapeutic strategies. Along other well-studied mechanisms, the secretion of extracellular vesicles (EVs) with antimicrobial capacities by neutrophils has gained more attention within the past years. Previous studies reported that neutrophil-derived EVs can inhibit A. fumigatus growth ex vivo; however, the molecular arsenal within these EVs remains poorly understood. In particular, this includes the putative contribution of EV-associated RNAs to the antifungal effect. Furthermore, we lack deeper knowledge about differential RNA processing within host cells in response to fungal infections and possible implications on the extracellular RNA landscape. My PhD project seeks to explore the role of extracellular RNA during fungal infections by focusing on different aspects: (1) the transcriptomic and epitransciptomic response of human (immune) host cells to A. fumigatus and other fungal pathogens, including the definition of common and species-specific responses; (2) the mechanism of extracellular vesicle loading with cargo RNA and their secretion, possibly steered by the (epi)transcriptomic response; (3) characterization of RNA-mediated antifungal effects of human EVs, including the determination of the involved cargo and target RNAs. We hope this project will, eventually, help pave the way for the application of EVs as delivery vectors for new RNA-based antifungals. Relevance to the field of Microbial Communication: EVs are secreted by both host cells and microbial pathogens. With their diverse cargo, including various types of RNAs, they may serve as a potent mode of communication, which may act both within one species as well as across species or kingdoms. An increasing number of studies acknowledge the relevance of EVs in the context of (fungal) infections. In this sense, my PhD thesis is centered on a key aspect of Microbial Communication of emerging importance.

PhD start: 11/01/2025