Peroxiredoxin 5 induction in response to PRRSV infection restricts viral proliferation by inhibiting lipid biosynthesis.

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV), a globally significant arterivirus, is known to cause respiratory disease accompanied by redox imbalance. In this study, we observed an increase in peroxiredoxin 5 (PRDX5), the only atypical 2-Cys PRDX with multifunctional properties, following PRRSV infection. Among PRRSV-encoded proteins, nonstructural protein 4 was identified as the most potent inducer of PRDX5 expression. Further investigation revealed that reactive oxygen species (ROS) induced by PRRSV infection or nsp4 overexpression were responsible for this upregulation of PRDX5, representing a host defense mechanism to mitigate excessive ROS production. Interestingly, PRDX5 upregulation was shown to inhibit lipid synthesis through the inactivation of the AMPK-ACC1 pathway, a key regulator of fatty acid biosynthesis, which occurred independently of PRDX5's peroxidase activity. Importantly, PRDX5 significantly suppressed PRRSV proliferation, and the exogenous addition of lipids restored viral multiplication, suggesting that PRDX5 exerts its antiviral effects by disrupting lipid production. Mechanistically, PRDX5 inhibited PRRSV infection by antagonizing viral release stage. These findings highlight PRDX5 as a critical host factor that counteracts PRRSV infection, providing new insights into antiviral strategies from a redox perspective.