MUC16-dependent Renal Vascular Adhesion of Candida Promotes Tissue Invasion and Predicts Clinical Outcome in Candidemia

Abstract Bloodstream infection with Candida species is associated with high mortality, yet the molecular basis of vascular adhesion and invasion remains unclear. We identify the endothelial surface mucin MUC16 as a key host factor enabling fungal vascular adherence. The MUC16 SEA domain directly engages the Candida adhesin Als3p and endothelial N-cadherin to form a ternary complex that promotes endothelial attachment and vascular invasion. Genetic deletion of Muc16 in mice markedly reduced fungal vascular binding, renal fungal burden, and Ly6Ghi CD11b+ neutrophil recruitment following intravenous infection, and diminished oral colonization in an oral model. Inflammatory induction of MUC16 occurred via MINCLE-, TLR9-, and Dectin-1–dependent signaling, converging on CARD9. In clinical cohorts, a MUC16 T10155I variant and elevated circulating MUC16 were associated with increased 30-day mortality. These findings establish MUC16 as a mechanistic link between endothelial sensing and Candida vascular invasion, with prognostic relevance in candidemia.