NKp46 Recognizes the Hyphal Form of Candida albicans and Mediates Protective Antifungal Immunity

Candida albicans is an opportunistic fungal pathogen capable of transitioning between yeast and hyphal forms, a morphological plasticity critical for its pathogenicity. Natural killer (NK) cells play a crucial role in antifungal immunity, yet the molecular basis of their interaction with C. albicans remains incompletely understood. Here, we identify NKp46 (NCR1 in mice), an activating receptor on NK cells, as a functional receptor for the hyphal--but not yeast--form of C. albicans. Using image flow cytometry and binding assays with NKp46-Ig and NCR1-Ig fusion proteins, we demonstrate that NKp46 selectively binds to hyphae. This interaction is mediated by the D2 domain of NKp46 and is sialic acid independent. Blocking NKp46 impairs NK cell degranulation and fungal killing in vitro. In vivo, mice deficient in NCR1 exhibit increased susceptibility to systemic C. albicans infection. Our findings establish NKp46 as a key sensor of invasive fungal morphology and underscore its role in early antifungal immunity.