Effect of resveratrol on herpesvirus encephalitis: Evidences for its mechanisms of action

Background: Herpes simplex virus type 1 (HSV-1)-induced herpes simplex encephalitis (HSE) has a high mortality rate in clinically immunocompromised patients, while recovered patients often experience neurological sequelae due to neuroinflammation. Nucleoside drugs and nucleoside analogues such as acyclovir and ganciclovir are mainly used in clinical treatment, and the emergence of resistant viral strains makes the development of new anti-herpesvirus encephalitis drugs urgent. Resveratrol is a multifunctional, plant-derived bioactive compound and its antiviral potential is attracting much attention. Purpose: This study aimed to investigate the anti-HSV-1 mechanism of resveratrol in microglial cells and in the HSE mouse model. Methods: The antiviral effect of resveratrol on HSV-1 infection was investigated by plaque assay, virus titer, immunofluorescence, Western blot and time-of-addition assay. The influence of resveratrol on stimulator of interferon gene (STING)/Nuclear Factor kappa B (NF-kappa B) signaling pathway-mediated neuroinflammation was examined by Western blot, RT-qPCR and ELISA. The interaction between resveratrol and STING/heat shock protein 90 beta (HSP90 beta) was evaluated by molecular modeling, co-immunoprecipitation, and drug affinity responsive target stability assay. The therapeutic effect of resveratrol on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores.