木犀草素通过激活环磷酸鸟苷-腺苷酸单磷酸合酶介导的抗病毒先天免疫来抑制单纯疱疹病毒 1 感染。

Luteolin inhibits herpes simplex virus 1 infection by activating cyclic guanosine monophosphate-adenosine monophosphate synthase-mediated antiviral innate immunity.

机构信息

Institute of Biomedicine, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Key Laboratory of innovative technology research on natural products and cosmetics raw materials, Jinan University, Guangzhou 510632, China.

出版信息

Phytomedicine. 2023 Nov;120:155020. doi: 10.1016/j.phymed.2023.155020. Epub 2023 Aug 17.

DOI:10.1016/j.phymed.2023.155020

PMID:37632997

Abstract

BACKGROUND

The successive outbreaks of large-scale infectious diseases due to virus infection have been a major threat to human health in recent decades. Herpes simplex virus I (HSV-1) is a widely-disseminated DNA virus that infects the central nervous system to cause herpes labialis, keratitis and herpes simplex virus encephalitis (HSE), resulting in recurrent lifelong clinical or subclinical episodes. Luteolin is a plant flavone that has been extensively used in the treatment of various human diseases, including carcinogenesis, inflammation and chronic degenerative diseases.

PURPOSE

The aim of this study was to investigate the antiviral molecular mechanism of luteolin against HSV-1 infection in vitro and in vivo.

METHODS

The antiviral effect of luteolin in cell lines was examined by viral plaque assay, RT-qPCR, Western blot and time-of-addition assay. The interaction between luteolin and cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) was evaluated by molecular modeling and semi-denaturing detergent agarose gel electrophoresis. The efficacy of luteolin on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. Cytokine expression and protein levels were examined by RT-qPCR, Western blot and ELISA.

RESULTS

Luteolin inhibited the early process of HSV-1 infection, without affecting the infection of acyclovir-resistant HSV-1 strains. In addition, luteolin enhanced antiviral type I interferon production and activated the cytoplasmic DNA-sensing cGAS-stimulator of interferon gene (STING) pathway. Luteolin directly bound the active substrate binding site and promoted the oligomerization of cGAS. Luteolin also inhibited HSE-related weight loss, neurodegeneration and neuroinflammation in mice caused by HSV-1 infection. Furthermore, luteolin enhanced type I interferon expression and stimulated the cGAS-STING signaling pathway in vivo.

CONCLUSION

Luteolin inhibited the post-entry process of HSV-1 by activating the cGAS-STING pathway to promote antiviral interferon production. These results provided the rationale for luteolin as a potent cGAS activator and antiviral agent.

摘要

背景

近几十年来，由于病毒感染引起的大规模传染病接连爆发，一直是人类健康的重大威胁。单纯疱疹病毒 I（HSV-1）是一种广泛传播的 DNA 病毒，感染中枢神经系统会导致唇疱疹、角膜炎和单纯疱疹病毒脑炎（HSE），导致复发性终生临床或亚临床发作。木犀草素是一种植物类黄酮，已广泛用于治疗各种人类疾病，包括致癌、炎症和慢性退行性疾病。

目的

本研究旨在探讨木犀草素体外和体内抗 HSV-1 感染的抗病毒分子机制。

方法

通过病毒斑形成试验、RT-qPCR、Western blot 和时间添加试验检测木犀草素在细胞系中的抗病毒作用。通过分子建模和半变性去污剂琼脂糖凝胶电泳评估木犀草素与环鸟苷酸-腺苷酸单磷酸合酶（cGAS）的相互作用。通过分析体重减轻、神经退行性症状和组织病理学评分，在 HSE 小鼠模型中评估木犀草素对 HSE 的疗效。通过 RT-qPCR、Western blot 和 ELISA 检测细胞因子表达和蛋白质水平。

结果

木犀草素抑制 HSV-1 感染的早期过程，而不影响阿昔洛韦耐药 HSV-1 株的感染。此外，木犀草素增强了抗病毒 I 型干扰素的产生，并激活了细胞质 DNA 感应 cGAS-干扰素基因刺激物（STING）途径。木犀草素直接结合活性底物结合位点并促进 cGAS 的寡聚化。木犀草素还抑制了 HSV-1 感染引起的小鼠 HSE 相关体重减轻、神经变性和神经炎症。此外，木犀草素在体内增强了 I 型干扰素的表达并刺激了 cGAS-STING 信号通路。