On September 17,Science Advances published online the collaborative research "Targeting lysophospholipid acid receptor 1 and ROCK kinases promotes antiviral innate immunity" by Wang Hongyan's group from Hangzhou Institute for Advanced Study (HIAS), UCAS/Center for Excellence in Molecular Cell Science (CEMCS), CAS (formerly known as Shanghai Institute of Biochemistry and Cell Biology). According to research, targeting LPA1 receptors belonging to the G protein-coupled receptor family and downstream ROCK kinases can promote the production of type I or III interferon in various cell types such as epithelial cells and macrophages, providing a new drug target for improving host resistance to viral infection.
Macrophages and epithelial cells in the host play an important role in the control of viral infection. They activate the transcription factor IRF3 and produce interferon by recognizing the components of the virus. Wang's group is particularly concerned with the functions and mechanisms of lipid and cholesterol metabolites in regulating host innate immunity and antiviral responses. Lysophosphatidic acid (LPA) is a lipid signaling molecule that can promote cell migration and cell proliferation. Other research groups have found that LPA increases significantly in the plasma of patients with SARS-CoV-2 or chronic hepatitis C virus infection, but it has not been reported whether it regulates the innate immune antiviral response.
In this study, a variety of viruses and viral nucleic acid mimics were used to treat macrophages, epithelial cells, fibroblasts, etc. It was found that the expression of LPA1 receptors was increased and LPA binding to LPA1 receptor could inhibit the production of type I/III interferon and reduce viral replication. Inhibitors or preclinical drugs that target LPA1 can promote the production of interferon by intestinal epithelial-derived organs and macrophages to resist viral infection. More importantly, LPA1 and the receptor ACE2 of SARS-CoV-2 colocalize in the small intestine and lung, suggesting that drugs targeting LPA1 can specifically act on the main organs infected by SARS-CoV-2. Mice treated with LPA1 inhibitor or Lpa1-specific knockout in intestinal epithelial cells can promote the host's ability to resist viral infection. Mechanistic studies have revealed that the LPA1 receptor activates ROCK kinase through G12/13, and ROCK phosphorylates the inhibitory site Ser97 of transcription factor IRF3, thus downregulating the activation of IRF3. Inhibition of ROCK kinase can promote IRF3 activation and interferon production, resulting in improved survival in virus-infected mice. Preclinical drugs targeting LPA1 inhibition have been developed to treat fibrosis in the lung or liver. Our findings reveal the new use of the drug in improving antiviral innate immunity, offering new strategies for treating infections such as SARS-CoV-2.
Co-first authors include Zhang Chi, a postdoctoral fellow from HIAS, UCAS, and Li Weiyun, assistant professor from the School of Life Sciences, Xiamen University. Co-corresponding authors include Wang Hongyan, a research fellow from HIAS, UCAS/Shanghai Institute of Biochemistry and Cell Biology (SIBCB), Wang Jianwei, a research fellow from Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), and Prof. Wei Bin from Shanghai University. Special thanks to Lei Xiaobo, a research fellow from CAMS & PUMC, Li Jinsong, Sun Bing and Chen Jianfeng, research fellows from SIBCB, Zhai Qiwei and Qin Jun, research fellows from Shanghai Institute of Nutrition and Health, CAS for their help. This study was completed with the strong support of the molecular biology technology platform, cell analysis technology platform, and laboratory animal platform of CEMCS and Bio-Research Innovation Center Suzhou. Special thanks also to the National Natural Science Foundation of China, the Ministry of Science and Technology, and the CAS Strategic Priority Research Program for their financial support.
