Mucoricin binding to β-glucan sites on germinating Mucorales spores disrupts neutrophil swarming to promote pathogenicity

Mucormycosis is an emerging, life-threatening infection caused by Mucorales fungi with incompletely understood immunopathogenesis. We found that unlike other fungal pathogens, Mucorales trigger coordinated neutrophil clustering (swarming) upon swelling of fungal spores. Neutrophil swarms efficiently eliminate germinating Mucorales via ROS production, upon sensing of β-glucan by complement receptor 3 (CR3). Impaired neutrophil clustering in mucormycosis-predisposing conditions, allows for mucoricin toxin production by germinating Mucorales. Released mucoricin selectively binds to β-glucan on the surface of Mucorales, creating a molecular trap that induces neutrophil apoptosis and swarming disruption, leading to invasive fungal disease. Suppression of mucoricin, either genetically or physiologically by albumin-bound free fatty acids, stabilizes neutrophil clusters leading to abrogation of fungal pathogenicity. Additionally, prophylactic GM-CSF administration prevents mucoricin-induced neutrophil death, and protects mice from mucormycosis. Our work identifies neutrophil swarming as the primary target of mucoricin and provides compelling evidence for therapeutic harnessing of this pathway to improve mucormycosis outcome.