Porcine serum amyloid A2 blocks PRRSV by directly targeting virion-associated PIP2 and GP5

Porcine reproductive and respiratory syndrome virus (PRRSV) is a significant pathogen in swine, causing substantial economic losses globally. The host acute-phase response to PRRSV infection and its role in antiviral defense remain poorly understood. In this study, we identify serum amyloid A2 (SAA2) as a key acute-phase protein that is induced during PRRSV infection and demonstrate its potent antiviral activity against this virus. While both SAA2 and SAA3 were upregulated in PRRSV-infected primary porcine alveolar macrophages, functional analyses revealed that SAA2 exerted anti-PRRSV effects. Both the ectopic expression of SAA2 and treatment with recombinant SAA2 protein significantly inhibited PRRSV replication in cultured cells. Mechanistically, SAA2 directly binds to PRRSV particles through interactions with phosphatidylinositol 4,5-bisphosphate (PIP2), a host-derived lipid membrane component in the virus particles, as well as the major envelope glycoprotein GP5. The anti-PRRSV activity of SAA2 was counteracted by high-density lipoprotein (HDL), revealing a physiological regulatory mechanism. Structure-function analysis further identified the N-terminal α-helix (encoded by exon 1) as essential for SAA2-mediated viral inhibition. Our findings unveil a novel antiviral strategy in which a host acute-phase protein directly targets enveloped virions, highlighting SAA2 as a potential target for intervention against PRRSV.