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

Huang，Ziwei1; Li，Shan1; Zhong，Lishan2; Su，Yuan2; Li，Menghe3,4; Wang，Xiaohui2; Wang，Zexu2; Wang，Zhiping1; Ye，Cuifang3,4; Ren，Zhe3,4; Wang，Xiao5; Zeng，Qiongzhen6,7; Zheng，Kai8; Wang，Yifei1,2

2024-05-01

10.1016/j.phymed.2024.155476

Phytomedicine   影响因子和分区

0944-7113

1618-095X

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-κB) signaling pathway-mediated neuroinflammation was examined by Western blot, RT-qPCR and ELISA. The interaction between resveratrol and STING/heat shock protein 90 beta (HSP90β) 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. Results: Resveratrol inhibited the early process of HSV-1 infection, and interfered with the STING/NF-κB signaling pathway to attenuate HSV-1-induced neuroinflammation and microglial M1 polarization, independent of its classical target Sirtuin1. Mechanistically, resveratrol completely bound to Glu515 and Lys491 of HSP90β, thus disrupting the HSP90β-STING interaction and promoting STING degradation. Resveratrol also significantly alleviated viral encephalitis and neuroinflammation caused by HSV-1 in the HSE mouse model. Conclusion: Resveratrol acted as a non-classical HSP90β inhibitor, binding to the STING-HSP90β interaction site to promote STING degradation and attenuate HSV-1-induced encephalitis and neuroinflammation. These findings suggest the alternative strategy of targeting HSP90β and resveratrol-mediated inhibition of HSP90β as a potential antiviral approach.

Herpes simplex encephalitis HSP90β Neuroinflammation Resveratrol STING/NF-κB

SCI

英语

其他

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85186571293

Scopus

1.Guangdong Provincial Engineering,Center of Topical Precise Drug Delivery System,School of Pharmacy,Guangdong Pharmaceutical University,Guangzhou,510006,China
2.Institute of Biomedicine,Guangdong Province Key Laboratory of Bioengineering Medicine,Key Laboratory of innovative technology research on natural products and cosmetics raw materials,College of Life Science and Technology,Jinan University,Guangzhou,510632,China
3.Department of Cell Biology,College of Life Science and Technology,Jinan University,Guangzhou,China
4.Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center,Guangzhou,510632,China
5.Department of Pharmacy,Shenzhen People's Hospital,The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,518020,China
6.Guangdong Provincial Clinical Research Center for Geriatrics,Shenzhen Clinical Research Center for Geriatrics,Shenzhen People's Hospital (The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,518020,China
7.Integrated Chinese and Western Medicine Postdoctoral Research Station,Jinan University,Guangzhou,510632,China
8.School of Pharmacy,Shenzhen University Medical School,Shenzhen University,Shenzhen,518055,China

Huang，Ziwei,Li，Shan,Zhong，Lishan,et al. Effect of resveratrol on herpesvirus encephalitis: Evidences for its mechanisms of action[J]. Phytomedicine,2024,127.

Huang，Ziwei.,Li，Shan.,Zhong，Lishan.,Su，Yuan.,Li，Menghe.,...&Wang，Yifei.(2024).Effect of resveratrol on herpesvirus encephalitis: Evidences for its mechanisms of action.Phytomedicine,127.

Huang，Ziwei,et al."Effect of resveratrol on herpesvirus encephalitis: Evidences for its mechanisms of action".Phytomedicine 127(2024).