Entomopathogenic fungi serve as powerful regulators of insect populations in nature. However, how immune effectors combat fungal pathogens remains incompletely understood. We employ Drosophila melanogaster as a genetically tractable model to dissect immune defense mechanisms against diverse fungal pathogens. We show 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-obligate fungus Entomophthora muscae employs a vegetative development strategy to hide from the host immune response. These findings reveal that Drosophila immune mechanisms effectively defend against a broad range of fungal pathogens, while highlighting striking adaptations to overcome these defenses in highly specialized fungal pathogens such as E. muscae.
Liu et al. (2026) studied this question.