Porcine enteric coronaviruses, including transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV), have caused enormous economic losses to the global pig industry. Unfortunately, new variants emerge of these viruses will make it difficult for pigs vaccinated with the appropriate vaccine to develop protective immunity. Hence, it is urgent to explore effective therapeutic agents and targets against these viruses. Capsaicin is an active compound found in plants of the Capsicum genus (prevention and/or treatment of pain, hypertension and inflammation), but little is known about its effects on enterovirus infections. Herein, we used porcine enteric coronavirus TGEV as a model to evaluate the antiviral activity of capsaicin and discovered that capsaicin inhibited the replication phase of TGEV. Mechanistically, calcium signaling pathway participates in the capsaicin-mediated antiviral function. Importantly, capsaicin treatment impaired the viral replication by attenuating cytosolic calcium, and supplementation with CaCl reduced the inhibitory effect of capsaicin on TGEV infection. Finally, we revealed that TRPV4 plays an essential role in modulating calcium ion influx in IPEC-J2 cells, and capsaicin inhibits TGEV replication by decreasing calcium ion influx through inhibition of TRPV4. Overall, our data suggest that capsaicin is a promising small molecular drug candidate for strengthening host resistance to porcine enteric coronavirus infection.
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