2. Academic Validation
  3. Reducing lipid peroxidation attenuates stress-induced susceptibility to herpes simplex virus type 1

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

  • Acta Pharmacol Sin. 2023 May 16;1-11. doi: 10.1038/s41401-023-01095-6.
Jing-Yu Weng # 1 2,  Xin-Xing Chen # 1 2,  Xiao-Hua Wang # 1 2,  Hui-Er Ye 1 2,  Yan-Ping Wu 1 2,  Wan-Yang Sun 1 2,  Lei Liang 1 2,  Wen-Jun Duan 1 2,  Hiroshi Kurihara 1 2,  Feng Huang 3,  Xin-Xin Sun 4,  Shu-Hua Ou-Yang 5 6,  Rong-Rong He 7 8 9,  Yi-Fang Li 10 11
Affiliations

Affiliations

  • 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.
  • 5 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. shouyang@jnu.edu.cn.
  • 6 Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China. shouyang@jnu.edu.cn.
  • 7 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. rongronghe@jnu.edu.cn.
  • 8 Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China. rongronghe@jnu.edu.cn.
  • 9 School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, Kunming, 650500, China. rongronghe@jnu.edu.cn.
  • 10 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. liyifang706@jnu.edu.cn.
  • 11 Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China. liyifang706@jnu.edu.cn.
  • # Contributed equally.
PMID: 37193755 DOI: 10.1038/s41401-023-01095-6
Abstract

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 (100 μM) significantly increased the cell viability, and inhibited CORT-induced elevation in the expression of Viral Proteins and genes. We demonstrated that CORT (50 μM) 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.

Keywords

Herpes simplex virus type 1; STING; arachidonate lipoxygenase 15; corticosterone; neuronal cells; phospholipid peroxidation; rosmarinic acid; stress; viral infection.

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