Tight junction suppression by candidalysin promotes gut-to-blood dissemination of Candida albicans.

BACKGROUND: The commensal fungus Candida albicans, a natural inhabitant of the human gut, can transition to a pathogenic state and disseminate into the blood. Disruption of the intestinal mucosal barrier, particularly through the impairment of epithelial cell integrity and intercellular junctions, is a critical step in this dissemination process. While candidalysin is a pore-forming cytolytic peptide encoded within ECE1 (extent of cell elongation 1 gene), its relationship to the abundance and organization of specific intestinal tight-junction proteins during dissemination remains incompletely defined.

METHODOLOGY/PRINCIPAL FINDINGS: A murine model and human colonic epithelial cells (NCM-460) were used to investigate the effect of candidalysin on fungal dissemination and its association with changes in tight-junction protein abundance and distribution. In vivo, infection with a candidalysin-deficient C. albicans mutant preserved TJ architecture, substantially reduced pro-inflammatory cytokine responses, and substantially reduced the frequency and amount of detectable fungal DNA in blood. In contrast, infection caused by wild-type (WT) and ECE1-reconstituted strains resulted in elevated serum levels of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α, accompanied by reduced protein expressions of the TJ components (ZO-1, Occludin, and Claudin-1). In vitro, experiments using purified candidalysin demonstrated a biphasic, dose-dependent effect on TJ proteins. At 3.125 μg/mL, TJ-associated signals were preserved and selected protein measurements were modestly increased, whereas transcript levels showed a slight reduction. At higher concentrations (≥12.5 μg/mL, up to 50 μg/mL), higher candidalysin concentrations were associated with pronounced loss and discontinuity of TJ-associated signals and reduced abundance of selected TJ proteins.

CONCLUSION/SIGNIFICANCE: The dose-dependent effects of candidalysin on epithelial junction-associated proteins support a context-dependent contribution to intestinal pathogenesis. These findings associate candidalysin with epithelial injury and dissemination in the present model but do not establish a binary molecular switch or a candidalysin-exclusive mechanism. Elucidating how candidalysin coordinates epithelial and immune pathways provides new insight into the mechanisms that sustain gut-fungal symbiosis and may reveal therapeutic targets to preserve mucosal integrity and prevent systemic candidiasis.