PPAR-δ of orange-spotted grouper exerts antiviral activity against fish virus and regulates interferon signaling and inflammatory factors

Peroxisome proliferator-activated receptor delta (PPAR-delta), also called PPAR-beta or PPAR-beta/delta, is a member of the peroxisome proliferator-activated receptor (PPAR) family, which belongs to the nuclear steroid receptor superfamily. Activated PPARs participate in the regulation of lipid and glucose metabolism and also affect cellular proliferation, differentiation, and apoptosis, and the immune responses. To investigate the roles of PPAR-delta in Singapore grouper iridovirus (SGN) infection, we cloned and characterized the gene encoding a PPAR-delta homologue from the orange-spotted grouper, Fpinephelus coioides (EcPPAR-delta). EcPPAR-delta encodes a 514-amino-acid polypeptide, with 95.29% and 74.76% homologue to the Serioia dumerili and human proteins, respectively. EcPPAR-delta contains a typical DNA-binding domain and a ligand-binding domain. Its expression was induced by SGIV infection in vitro. A subcellular localization analysis showed that EcPPAR-delta localizes throughout the cytoplasm and nucleus, with a diffuse intracellular expression pattern. SGIV replication was reduced by EcPPAR-delta overexpression, which was evident in the reduced severity of the cytopathic effect, reduced viral gene transcription, and the reduced expression of the viral capsid protein. The replication of SGIV increased with the knockdown of EcPPAR-delta. The overexpression and silencing of EcPPAR-delta in grouper spleen cells showed that EcPPAR-delta plays a positive role in the regulation of the interferon signaling pathway, but has an anti-inflammatory effect on the inflammatory response. The anti-inflammatory effect of EcPPAR-delta may be related to its function in maintaining cell homeostasis. Because the interferon signaling pathway plays an important role in antiviral immune responses, we speculate that the activation of the interferon signaling pathway by EcPPAR-delta overexpression underlies its inhibitory effect on SGN replication. Together, our data greatly extend our understanding of the roles of the EcPPAR-delta family members in the pathogenesis of fish viruses.