RT Journal Article SR Electronic T1 Conidial melanin of the human pathogenic fungus Aspergillus fumigatus disrupts cell autonomous defenses in amoebae JF bioRxiv FD Cold Spring Harbor Laboratory SP 730879 DO 10.1101/730879 A1 Iuliia Ferling A1 Joe Dan Dunn A1 Alexander Ferling A1 Thierry Soldati A1 Falk Hillmann YR 2019 UL http://biorxiv.org/content/early/2019/08/09/730879.abstract AB The human pathogenic fungus Aspergillus fumigatus is a ubiquitous saprophyte that causes fatal infections in immunocompromised individuals. Following inhalation, conidia are ingested by innate immune cells and can arrest phagolysosome maturation. How such general virulence traits could have been selected for in natural environments is unknown. Here, we used the model amoeba Dictyostelium discoideum to follow the antagonistic interaction of A. fumigatus conidia with environmental phagocytes in real time. We found that conidia covered with the green pigment 1,8-dihydroxynaphthalene-(DHN)-melanin were internalized at far lower rates when compared to those lacking the pigment, despite high rates of initial attachment. Immediately after uptake of the fungal conidia, nascent phagosomes were formed through sequential membrane fusion and fission events. Using single-cell assays supported by a computational model integrating the differential dynamics of internalization and phagolysosome maturation, we could show that acidification of phagolysosomes was transient and was followed by neutralization and, finally, exocytosis of the conidium. For unpigmented conidia, the cycle was completed in less than 1 h, while the process was delayed for conidia covered with DHN-melanin. At later stages of infection, damage to infected phagocytes triggered the ESCRT membrane repair machinery, whose recruitment was also attenuated by DHN-melanin, favoring prolonged persistence and the establishment of an intracellular germination niche in this environmental phagocyte. Increased exposure of DHN-melanin on the conidial surface also improved fungal survival when confronted with the fungivorous predator Protostelium aurantium, demonstrating its universal antiphagocytic properties.