Stimulating the autophagic-lysosomal axis enhances host defence against fungal infection in a zebrafish model of Invasive Aspergillosis

The increasing prevalence of antifungal-resistant human pathogenic fungi, particularly azole-resistant Aspergillus fumigatus, is a life-threatening challenge to the immunocompromised population. Autophagy-related processes have been shown to be activated in the host response against fungal infection, but their overall effect in host survival remains uncertain. To analyze the relevance of these processes, we studied the in vivo host-pathogen interaction between innate immune phagocytes and A. fumigatus conidia during the first hours of infection in a zebrafish animal model of Invasive Aspergillosis. We visualize the autophagy-related processes in innate immune cells in vivo shortly after phagocytosis and report differential Lc3 recruitment in macrophages and neutrophils. We also confirm the involvement of these autophagy processes to the overall host survival to the infection and how both genetic (dram1-mediated) and pharmacological stimulation via three independent autophagy pathways improves the host survival against A. fumigatus infection in vivo. Therefore, we provide proof of concept that stimulating the (auto)phagolysosomal pathways is a promising approach to develop host-directed therapies against Invasive Aspergillosis, and should be explored further either as prophylactic, adjunctive, or standalone treatment in settings with high prevalence of drug-resistant Aspergillus infections.