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

Wang，Yuan1; Li，Feng1,2; Wang，Zexu1; Song，Xiaowei1; Ren，Zhe1,4; Wang，Xiao5; Wang，Yifei1,4; Zheng，Kai3

2023-11-01

10.1016/j.phymed.2023.155020

Phytomedicine   Impact Factor & Quartile

0944-7113

1618-095X

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.

Antiviral immune response cGAS-STING HSE HSV-1 Luteolin

SCI

English

Corresponding

Basic and Applied Basic Research Foundation of Guangdong Province[2021B1515120088];National Natural Science Foundation of China[81872908];National Natural Science Foundation of China[82072274];

Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine

Plant Sciences ; Chemistry, Medicinal ; Integrative & Complementary Medicine ; Pharmacology & Pharmacy

WOS:001067327800001

ELSEVIER GMBH

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85168740531

Scopus

1.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
2.Infectious Diseases Institute,Guangzhou Eighth People's Hospital,Guangzhou,510440,China
3.School of Pharmacy,Shenzhen University Medical School,Shenzhen University,Shenzhen,518055,China
4.Guangdong Provincial biotechnology drug & Engineering Technology Research Center,National Engineering Research Center of Genetic Medicine,National Engineering Research Centre for Modernization of Chinese Medicine,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

Wang，Yuan,Li，Feng,Wang，Zexu,et al. Luteolin inhibits herpes simplex virus 1 infection by activating cyclic guanosine monophosphate-adenosine monophosphate synthase-mediated antiviral innate immunity[J]. Phytomedicine,2023,120.

Wang，Yuan.,Li，Feng.,Wang，Zexu.,Song，Xiaowei.,Ren，Zhe.,...&Zheng，Kai.(2023).Luteolin inhibits herpes simplex virus 1 infection by activating cyclic guanosine monophosphate-adenosine monophosphate synthase-mediated antiviral innate immunity.Phytomedicine,120.

Wang，Yuan,et al."Luteolin inhibits herpes simplex virus 1 infection by activating cyclic guanosine monophosphate-adenosine monophosphate synthase-mediated antiviral innate immunity".Phytomedicine 120(2023).