Reducing lipid peroxidation attenuates stress-induced susceptibility to herpes simplex virus type 1  

作　　者：Jing-yu Weng Xin-xing Chen Xiao-hua Wang Hui-er Ye Yan-ping Wu Wan-yang Sun Lei Liang Wen-jun Duan Hiroshi Kurihara Feng Huang Xin-xin Sun Shu-hua Ou-Yang Rong-rong He Yi-fang Li 

机构地区：[1]Guangdong Engineering Research Center of Chinese Medicine&Disease Susceptibility,International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education(MOE),College of Pharmacy,Jinan University,Guangzhou,510632,China [2]Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research,College of Pharmacy,Jinan University,Guangzhou,510632,China [3]School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization,Yunnan University of Chinese Medicine,Kunming,650500,China [4]Jiujiang Maternal and Child Health Hospital,Jiujiang,332000,China

出　　处：《Acta Pharmacologica Sinica》2023年第9期1856-1866,共11页中国药理学报（英文版）

基　　金：supported by the Natural Science Foundation of Guangdong (2023B1515040016 and 2021B1515120023);the National Natural Science Foundation of China (Grant numbers 82125038,82274123 and 82174054);the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y036);the Innovation Team Project of Guangdong Provincial Department of Education (2020KCXTD003)and GDUPS (2019);the National Key Research and Development Program of China (2022YFC0867400).

摘　　要：Psychological stress increases the susceptibility to herpes simplex virus type 1(HSV-1)infection.There is no effective intervention due to the unknown pathogenesis mechanisms.In this study we explored the molecular mechanisms underlying stress-induced HSV-1 susceptibility and the antiviral effect of a natural compound rosmarinic acid(RA)in vivo and in vitro.Mice were administered RA(11.7,23.4 mg·kg^(−1)·d^(−1),i.g.)or acyclovir(ACV,206 mg·kg^(−1)·d^(−1),i.g.)for 23 days.The mice were subjected to restraint stress for 7 days followed by intranasal infection with HSV-1 on D7.At the end of RA or ACV treatment,mouse plasma samples and brain tissues were collected for analysis.We showed that both RA and ACV treatment significantly decreased stress-augmented mortality and alleviated eye swelling and neurological symptoms in HSV-1-infected mice.In SH-SY5Y cells and PC12 cells exposed to the stress hormone corticosterone(CORT)plus HSV-1,RA(100μM)significantly increased the cell viability,and inhibited CORT-induced elevation in the expression of viral proteins and genes.We demonstrated that CORT(50μM)triggered lipoxygenase 15(ALOX15)-mediated redox imbalance in the neuronal cells,increasing the level of 4-HNE-conjugated STING,which impaired STING translocation from the endoplasmic reticulum to Golgi;the abnormality of STING-mediated innate immunity led to HSV-1 susceptibility.We revealed that RA was an inhibitor of lipid peroxidation by directly targeting ALOX15,thus RA could rescue stress-weakened neuronal innate immune response,thereby reducing HSV-1 susceptibility in vivo and in vitro.This study illustrates the critical role of lipid peroxidation in stress-induced HSV-1 susceptibility and reveals the potential for developing RA as an effective intervention in anti-HSV-1 therapy.

关 键 词：Herpes simplex virus type 1 STRESS CORTICOSTERONE arachidonate lipoxygenase 15 phospholipid peroxidation STING viral infection rosmarinicacid neuronal cells 

分 类 号：R96[医药卫生—药理学]