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.
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Acknowledgements
This study was partly 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), and the National Key Research and Development Program of China (2022YFC0867400). The authors (Rong-rong He and Yi-fang Li) also gratefully acknowledge the support of the K.C. Wong Education Foundation.
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YFL, RRH, and HK conceived and designed the research. JYW, XXC, XHW, and HEY performed the experiments. JYW, XXC, and XHW contributed to the acquisition and analysis of the data. JYW and SHOY prepared figures, tables, and the manuscript. YPW, WYS, LL, WJD. FH, XXS, and HK partly advised the research. YFL, RRH, and SHOY revised and approved the manuscript. All of the authors have approved the final manuscript.
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Weng, Jy., Chen, Xx., Wang, Xh. et al. Reducing lipid peroxidation attenuates stress-induced susceptibility to herpes simplex virus type 1. Acta Pharmacol Sin 44, 1856–1866 (2023). https://doi.org/10.1038/s41401-023-01095-6
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DOI: https://doi.org/10.1038/s41401-023-01095-6
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