Candidalysin meets the kynurenine pathway: a tale of damage and regulation

<p dir="ltr"><i>Candida albicans</i> is a commensal fungus that colonises the gastrointestinal tract and transitions from yeast to hyphal morphology during invasion. The hyphal form secretes candidalysin, which is a cytolytic peptide essential for disrupting epithelial barriers, invading tissue, and activating pro-inflammatory immune responses. The kynurenine pathway (KP) is the primary route for tryptophan catabolism and generates bioactive metabolites that modulate immune responses and inflammation. This pathway plays a pivotal role as mediator of gastrointestinal pathophysiology. This study hypothesised that candidalysin-induced inflammation activates the KP in intestinal epithelial Caco-2 cells and that KP metabolites contribute to immune modulation. The investigation examined candidalysin’s effects independently and in combination with IFN-γ, which is a known activator of indoleamine 2,3-dioxygenase enzyme, over 24- and 48-hour timepoints. The findings demonstrate that candidalysin induces epithelial damage as evidenced by LDH release, and stimulates cytokine production, including IL-6, MCP-1, and type-2 cytokines IL-5 and IL-13. Candidalysin also suppresses anti-inflammatory cytokines IL-4 and IL-10, indicating a shift toward a pro-inflammatory immune environment. While candidalysin alone activates the KP, co-treatment with IFN-γ amplified this activation by enhancing kynurenine-to-tryptophan ratios and downstream metabolite production. These findings establish candidalysin as both the driver of epithelial damage and a regulator of immune and metabolic pathways. Its effects in Caco-2 cells reveal a critical role for the KP in mediating the interplay between fungal virulence factors and epithelial immune responses.</p>