Drosophila host defense mechanisms against filamentous fungal pathogens with diverse lifestyles

Entomopathogenic fungi serve as powerful regulators of insect populations in nature. The infection outcome depends on the complex interplay between insect immune defenses and fungal adaptive strategies. However, how host immune effectors contribute to resist fungi with different ecological strategies remains incompletely understood. In this study, we employ Drosophila melanogaster as a genetically tractable model to dissect immune defenses against diverse fungal pathogens. Our study uncovers that the Toll pathway is the key determinant of immunity against all species tested regardless of their ecological strategy, primarily through resistance mechanisms that limit fungal proliferation. In addition, melanization, but not phagocytosis or the Imd pathway, also has a role in limiting fungal entry and proliferation. Additionally, we show that fungal protease detection by Persephone has a quantitatively more critical role than the glucan sensor GNBP3 in the activation of the Toll pathway upon fungal infection. Our study also reveals that the fly-specific obligate fungus Entomophthora muscae employs a vegetative development strategy, protoplasts, to hide from the host immune response. These findings reveal that Drosophila immune mechanisms effectively defend against a broad range of fungal pathogens with various ecological lifestyles, while highlighting striking adaptations to overcome these defenses in highly specialized fungal pathogens.