Dangerous liaisons: Candidalysin and myeloid cells in candidiasis

Candida albicans causes a broad spectrum of diseases in humans, ranging from noninvasive superficial infections, such as chronic mucocutaneous candidiasis, to life-threatening systemic infections [1].C. albicans produces candidalysin, a cytolytic peptide encoded by the ECE1 (extent of cell elongation 1) gene [2].Candidalysin is an amphipathic α-helical peptide containing two amyloidogenic regions.It is processed as the third peptide (Ece1-III) from the Ece1 protein by the proteases Kex2 and Kex1, which release the mature toxin into the extracellular environment [3].Expressed primarily during the filamentous growth phase, candidalysin integrates into epithelial cell membranes, a process facilitated by interactions with sulfated glycosaminoglycans (GAGs), driving barrier disruption and orchestrated immune recruitment in mouse models of oropharyngeal and vulvovaginal candidiasis [3,4].Candidalysin is also a potent host immune modulator.It triggers the secretion of pro-inflammatory cytokines and chemokines, most notably granulocyte-macrophage colony-stimulating factor (GM-CSF), which is essential for the migration and activation of myeloid cells [5,6].In immunocompromised patients, such as those with CARD9 deficiency, GM-CSF therapy has demonstrated significant potential in alleviating candidiasis [7,8].Furthermore, the depletion of myeloid cells promotes fungal proliferation and increases host mortality, underscoring their critical role in antifungal defense [9].While the foundational functions of candidalysin have been elegantly summarized previously [10], our understanding of its nuanced role in myeloid cell crosstalk continues to evolve.In this review, we synthesize current in vitro and in vivo findings on how this toxin coordinates complex interactions with myeloid cells, providing a framework to guide future research and therapeutic strategies in candidiasis.