Targeting lysophospholipid acid receptor 1 and ROCK kinases promotes antiviral innate immunity

Zhang, Chi; Li, Weiyun; Lei, Xiaobo; Xie, Zhenfei; Qi, Linlin; Wang, Hui; Xiao, Xia; Xiao, Jun; Zheng, Yuxiao; Dong, Chen; Zheng, Xin; Chen, Shiyang; Chen, Jianfeng; Sun, Bing; Qin, Jun; Zhai, Qiwei; Li, Jinsong; Wei, Bin; Wang, Jianwei; Wang, Hongyan

Growing evidence indicates the vital role of lipid metabolites in innate immunity. The lipid lysophosphatidic acid (LPA) concentrations are enhanced in patients upon HCV or SARS-CoV-2 infection, but the function of LPA and its receptors in innate immunity is largely unknown. Here, we found that viral infection promoted the G protein–coupled receptor LPA1 expression, and LPA restrained type I/III interferon production through LPA1. Mechanistically, LPA1 signaling activated ROCK1/2, which phosphorylated IRF3 Ser(97) to suppress IRF3 activation. Targeting LPA1 or ROCK in macrophages, fibroblasts, epithelial cells, and LPA1 conditional KO mice promoted interferon-induced clearance of multiple viruses. LPA1 was colocalized with the receptor ACE2 in lung and intestine. Together with previous findings that LPA1 and ROCK1/2 promoted vascular leaking or lung fibrosis, we propose that the current available preclinical drugs targeting the LPA1-ROCK module might protect from SARS-CoV-2 or various virus infections in the intestine or lung.