Surface expression of PEDV nucleocapsid protein facilitates NK cell-mediated ADCC via anti-N nonneutralizing antibody

The nucleocapsid (N) protein is the most abundant viral protein during porcine epidemic diarrhea virus (PEDV) infection and exhibits strong immunogenicity, prompting the host immune system to produce large quantities of antibodies against it. However, N-specific antibodies are non-neutralizing, as the N protein is typically located inside viral particles. Understanding the roles of N-specific antibodies during PEDV infection is crucial for developing more effective vaccines. In this study, we demonstrated that a significant amount of PEDV-N protein is expressed on the surface of living cells during PEDV infection or transient N expression. Mechanistically, the PEDV-N protein may reach the cell surface via the exosome secretion pathway. Furthermore, anti-N antibodies can bind to the surface N protein and induce antibody-dependent natural killer (NK) cell-mediated cytotoxicity (ADCC), directly killing PEDV-infected cells. Although anti-N antibodies lack neutralizing effects against PEDV infection, they can target the N protein present on the surface of PEDV-infected cells to induce NK cell-mediated ADCC, thus protecting the host from viral infection. Our results indicate that the N protein holds significant potential as a candidate for designing vaccines against porcine enteric viruses.