Hyperoside inhibits EHV-8 infection via alleviating oxidative stress and IFN production through activating JNK/Keap1/Nrf2/HO-1 signaling pathways

Equine herpesvirus type 8 (EHV-8) causes abortion and respiratory disease in horses and donkeys, leading to serious economic losses in the global equine industry. Currently, there is no effective vaccine or drug against EHV-8 Infection, underscoring the need for a novel Antiviral drug to prevent EHV-8-induced latent Infection and decrease the pathogenicity of this virus. The present study demonstrated that hyperoside can exert Antiviral effects against EHV-8 Infection in RK-13 (rabbit kidney cells), MDBK (Madin-Darby bovine kidney), and NBL-6 cells (E. Derm cells). Mechanistic investigations revealed that hyperoside induces heme oxygenase-1 expression by activating the c-Jun N-terminal kinase/nuclear factor erythroid-2-related factor 2/Kelch-like ECH-associated protein 1 axis, alleviating oxidative stress and triggering a downstream Antiviral interferon response. Accordingly, hyperoside inhibits EHV-8 Infection. Meanwhile, hyperoside can also mitigate EHV-8-induced injury in the lungs of infected mice. These results indicate that hyperoside may serve as a novel Antiviral agent against EHV-8 Infection.IMPORTANCEHyperoside has been reported to suppress viral infections, including herpesvirus, hepatitis B virus, infectious bronchitis virus, and severe acute respiratory syndrome coronavirus 2 Infection. However, its mechanism of action against equine herpesvirus type 8 (EHV-8) is currently unknown. Here, we demonstrated that hyperoside significantly inhibits EHV-8 adsorption and internalization in susceptible cells. This process induces HO-1 expression via c-Jun N-terminal kinase/nuclear factor erythroid-2-related factor 2/Kelch-like ECH-associated protein 1 axis activation, alleviating oxidative stress and triggering an Antiviral interferon response. These findings indicate that hyperoside could be very effective as a drug against EHV-8.

EHV-8 inhibitor; IFN response; JNK/Nrf2/ Keap1/HO-1; antioxidants; hyperoside.