PRRSV nucleocapsid and nonstructural proteins dual-regulate CD40 expression via ATF-2 and AP-1 pathways.

Abstract

Macrophage surface molecules critically regulate inflammatory responses. Porcine reproductive and respiratory syndrome virus (PRRSV), an immunosuppressive pathogen with marked tropism for porcine alveolar macrophages, modulates host surface receptor expression to facilitate infection. Here, we screened the expression of immunoregulatory molecules during PRRSV infection and identified CD40 as the most significantly upregulated transcript. We demonstrated that the PRRSV nucleocapsid protein (N) enhances CD40 promoter activity, whereas nonstructural proteins Nsp1α, Nsp11, and Nsp12 suppress it. Mechanistically, protein N upregulated CD40 via the transcription factor ATF-2, while Nsp1α, Nsp11, and Nsp12 downregulated CD40 through AP-1. CD40 overexpression restricted PRRSV replication, suggesting its potential as a target for antiviral strategies.