Fungal Phosphatase-Dependent Induction of Host Cell Pyroptosis by Candidalysin

Abstract Fungal infections pose a major public health threat and can cause host cell damage through diverse forms of regulated cell death. However, our understanding of how fungal pathogens interact with host to elicit pyroptosis remains in its infancy. Here, we show that candidalysin, the cytolytic peptide toxin of Candida albicans, induces cell type-specific pyroptosis in epithelial cells and macrophages through GSDME and GSDMD activation, respectively. Dynamic dual transcriptomic profiling of host–fungal interaction suggested associations of candidalysin-induced pyroptosis with CCND1 in macrophages and BHLHE40 in epithelial cells, together with shared changes in phosphatase-related genes in C. albicans. In vivo, C. albicans infection induced a biphasic pyroptosis in kidney, characterized by early Caspase-3-GSDME and later Caspase-1-GSDMD activation. Candidalysin deficiency reduced pyroptotic responses and increased host CCND1 expression, whereas CCND1 knockdown enhanced pyroptosis. Furthermore, PHO100-mediated phosphate regulation contributed to fungal growth and hyphal development under phosphate limitation and influenced host pyroptotic responses. Together, these findings highlight a potential role for fungal phosphate-related regulation in candidalysin-associated pyroptosis and C. albicans pathogenicity.