Ergosterol peroxide suppresses porcine deltacoronavirus (PDCoV)-induced autophagy to inhibit virus replication via p38 signaling pathway

Porcine deltacoronavirus (PDCoV) is a swine enteropathogenic coronavirus (CoV) that continues to spread globally, placing strain on economic and public health. Currently, the pathogenic mechanism of PDCoV remains largely unclear, and effective strategies to prevent or treat PDCoV infection are still limited. In this study, the interaction between autophagy and PDCoV replication in LLC-PK1 cells was investigated. We demonstrated that PDCoV infection induced a complete autophagy process. Pharmacologically induced autophagy with rapamycin increased the expression of PDCoV N, while pharmacologically inhibited autophagy with wortmannin decreased the expression of PDCoV N, suggesting that PDCoV-induced autophagy facilitates virus replication. Further experiments showed that PDCoV infection activated p38 signaling pathway to trigger autophagy. Besides, ergosterol peroxide (EP) alleviated PDCoV-induced activation of p38 to suppress autophagy, thus exerting its antiviral effects. Finally, we employed a piglet model of PDCoV infection to demonstrate that EP prevented PDCoV infection by suppressing PDCoV-induced autophagy via p38 signaling pathway in vivo. Collectively, these findings accelerate the understanding of the pathogenesis of PDCoV infection and provide new insights for the development of EP as an effective therapeutic strategy for PDCoV.