Candida albicans induces neutrophil extracellular traps and leucotoxic hypercitrullination via candidalysin

Abstract

The peptide toxin candidalysin, secreted by Candida albicans hyphae, promotes stimulation of neutrophil extracellular traps (NETs). However, candidalysin alone triggers a distinct mechanism for NET‐like structures (NLS), which are more compact and less fibrous than canonical NETs. Candidalysin activates NADPH oxidase and calcium influx, with both processes contributing to morphological changes in neutrophils resulting in NLS formation. NLS are induced by leucotoxic hypercitrullination, which is governed by calcium‐induced protein arginine deaminase 4 activation and initiation of intracellular signalling events in a dose‐ and time‐dependent manner. However, activation of signalling by candidalysin does not suffice to trigger downstream events essential for NET formation, as demonstrated by lack of lamin A/C phosphorylation, an event required for activation of cyclin‐dependent kinases that are crucial for NET release. Candidalysin‐triggered NLS demonstrate anti‐ Candida activity, which is resistant to nuclease treatment and dependent on the deprivation of Zn 2+ . This study reveals that C. albicans hyphae releasing candidalysin concurrently trigger canonical NETs and NLS, which together form a fibrous sticky network that entangles C. albicans hyphae and efficiently inhibits their growth. image The cytolytic peptide toxin candidalysin is secreted by the invasive hyphal form of the human fungal pathogen Candida albicans . This study investigates the intricate interaction of candidalysin and neutrophils. Candidalysin‐secreting hyphae are strong inducers, while candidalysin‐deficient hyphae are poor inducers of NETs. Candidalysin alone triggers neutrophils to release NET‐like structures (NLS) via ROS‐ and Ca 2+ ‐dependent pathways. While candidalysin hampers neutrophil function, the toxin also increases the capacity of neutrophils to restrict hyphal growth. These results provide context for discrepancies in prior studies observing C. albicans ‐induced DNA traps of neutrophils.