Resveratrol can inhibit porcine reproductive and respiratory syndrome virus infection in vitro and in vivo by inhibiting PI3K/Akt signaling pathway.

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically costly pathogens in global pig industry, causes reproductive dysfunction in pregnant sows and respiratory distress in piglets. Resveratrol (RES), a polyphenolic compound, exhibits antiviral properties. Despite its recognized bioactivity, the potential antiviral efficacy against PRRSV remains underexplored. This research investigated the effect of RES in PRRSV infection and its underlying molecular mechanism. The animal attack tests showed that RES markedly improved clinical symptoms and reduced lung tissue damage in piglets infected with PRRSV. In vitro experiments further revealed RES suppress PRRSV replication within Marc-145 cells. Mechanistic investigations revealed that the PI3K/Akt signaling pathway was the crucial passage. RES directly acted on PRRSV particles by down-regulating Nsp3, thereby effectively inhibiting viral replication in cells. Specifically, we identified the PYDP motif of Nsp3 as crucial for binding to the key protein p85 in the PI3K/Akt signaling pathway, highlighting a pivotal amino acid site for viral modulation of this pathway. Furthermore, in host cells, RES inhibited PRRSV replication by suppressing the PI3K/Akt pathway, involving coordinated regulation of autophagy and ferroptosis. Notably, RES directly suppressed viral replication by inhibiting autophagy and ferroptosis, with evident cross-talk between these processes. Collectively, our findings unveil a novel mechanism of the cross-talk between autophagy and ferroptosis in regulating PRRSV infection. RES exhibited inhibitory effects on PRRSV both in vivo and in vitro by targeting the PI3K/Akt pathway. These findings will provide important insights for developing prevention and treatment strategies against PRRS.