DHA and EPA inhibit porcine coronavirus replication by alleviating ER stress

The 2019 coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted significant gaps in our mechanisms to prevent and control cross-species transmission of animal coronaviruses. Porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine delta coronavirus (PDCoV) are common porcine coronaviruses with similar clinical features. In the absence of effective drugs and methods of prevention and control, outbreaks of these viruses have led to significant economic losses in the global pig industry. Here, we report the effect of five fatty acids against porcine coronaviruses: sodium butyrate, lauric acid, palmitic acid, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). DHA and EPA reduced viral replication by attenuating the endoplasmic reticulum stress and inhibiting PEDV, TGEV, and PDCoV infections in vero cells, PK-15 cells, and LLC-PK1 cells in vitro, respectively. Additionally, DHA and EPA increased the host antioxidant levels and reduced inflammation. In conclusion, we report here for the first time the antiviral effects of DHA and EPA on porcine coronaviruses and provide a molecular basis for the development of new fatty acid-based therapies to control porcine coronavirus infection and transmission. IMPORTANCE Porcine epidemic diarrhea caused by porcine coronaviruses remains a major threat to the global swine industry. Fatty acids are extensively involved in the whole life of the virus. In this study, we found that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) significantly reduced the viral load of porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine delta coronavirus (PDCoV) and acted on the replication of the viruses rather than attachment and entry. We further confirmed that DHA and EPA inhibited PEDV replication by alleviating the endoplasmic reticulum stress. Meanwhile, DHA and EPA alleviate PEDV-induced inflammation and reactive oxygen species (ROS) levels and enhance the cellular antioxidant capacity. These data indicate that DHA and EPA have antiviral effects on porcine coronaviruses and provide a molecular basis for the development of new fatty acid-based therapies to control porcine coronavirus infection and transmission.