Fungal hyphae instigate non-canonical inflammatory cell death in macrophages

Fungal pathogens annually claim around 1.5 million lives, for which they are increasingly recognized as a threat to human health. Protective antifungal immunity centrally involves innate phagocytes. Many fungi switch morphologies to overcome defences and cause disease. Filamentation, particularly for the polymorphic fungus Candida albicans , is tightly connected with tissue invasion, lytic escape from within phagocytes, toxin production, and pyroptosis. Current infection models often disregard the interactions between extracellular hyphae and phagocytes. Yet, here we reveal a previously overlooked mechanism of macrophage cell death during fungal infection. Upon hyphal recognition, macrophages undergo host-regulated, non-pyroptotic, inflammatory death (“hyphoptosis”) that stimulates vigorous neutrophil responses. We identified C-type lectin, integrin, PI3K and ROS signalling driving this macrophage-specific cell death, which can be alleviated by immunotherapeutic macrophage rewiring with GM-CSF or IL-4. Genetic variation in the pathway associated with candidemia, proposing that dysregulation of hyphoptosis impacts human susceptibility to live-threatening invasive candidiasis.