Abstract
Candida albicans is an opportunistic fungal pathogen whose ability to switch between yeast and hyphal forms is central to its virulence. Natural killer (NK) cells are critical components of innate antifungal defense, yet the mechanisms by which they detect fungal morphology have remained unclear. We show that NKp46 (NCR1 in mice), an activating receptor on NK cells, directly recognizes the hyphal form of C. albicans but not yeast. Using image flow cytometry and receptor-ligand binding assays with NKp46-Ig and NCR1-Ig fusion proteins, we demonstrate that NKp46 engagement is mediated through its D2 domain and is independent of sialic acid interactions. Functional blockade of NKp46 significantly reduces NK cell degranulation and fungal killing, while NCR1-deficient mice display heightened susceptibility to systemic candidiasis. These findings identify NKp46 as a critical sensor of fungal morphology and highlight its importance in shaping early antifungal immunity.