Volume 31, No 12, Dec 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 12, December 2021: 1230-1243   |  Open Access

ORIGINAL ARTICLES

SARS-CoV-2 promotes RIPK1 activation to facilitate viral propagation

Gang Xu^1,† , Ying Li^2,† , Shengyuan Zhang^1,† , Haoran Peng^3,† , Yunyun Wang^4,† , Dekang Li^2,5 , Taijie Jin² , Zhuohao He² , Yilun Tong^2,5 , Chunting Qi² , Guowei Wu^2,5 , Kangyun Dong² , Jizhou Gou⁶ , Yang Liu¹ , Tongyang Xiao¹ , Jing Qu⁷ , Liang Li^7,* , Liang Liu^4,* , Ping Zhao^3,* , Zheng Zhang^1,* , Junying Yuan^2,*

¹Institute of Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
²Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd, Pudong, Shanghai, China
³Department of Microbiology, Second Military Medical University, 800 Xiangyin Rd, Shanghai, China
⁴Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
⁵University of Chinese Academy of Sciences, Beijing, China
⁶Department for Pathology, Shenzhen Third People’s Hospital, Shenzhen, Guangdong, China
⁷Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Nanshan, Shenzhen, Guangdong, China
^†These authors contributed equally: Gang Xu, Ying Li, Shengyuan Zhang, Haoran Peng, Yunyun Wang
Correspondence: Liang Li(liang.li@siat.ac.cn)Liang Liu(907505@qq.com)Ping Zhao(pnzhao@163.com)Zheng Zhang(zhangzheng1975@aliyun.com)Junying Yuan(junying_yuan@sioc.ac.cn)

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the ongoing global pandemic that poses substantial challenges to public health worldwide. A subset of COVID-19 patients experience systemic inflammatory response, known as cytokine storm, which may lead to death. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important mediator of inflammation and cell death. Here, we examined the interaction of RIPK1-mediated innate immunity with SARS-CoV-2 infection. We found evidence of RIPK1 activation in human COVID-19 lung pathological samples, and cultured human lung organoids and ACE2 transgenic mice infected by SARS-CoV-2. Inhibition of RIPK1 using multiple small-molecule inhibitors reduced the viral load of SARS-CoV-2 in human lung organoids. Furthermore, therapeutic dosing of the RIPK1 inhibitor Nec-1s reduced mortality and lung viral load, and blocked the CNS manifestation of SARS-CoV-2 in ACE2 transgenic mice. Mechanistically, we found that the RNA-dependent RNA polymerase of SARS-CoV-2, NSP12, a highly conserved central component of coronaviral replication and transcription machinery, promoted the activation of RIPK1. Furthermore, NSP12 323L variant, encoded by the SARS-CoV-2 C14408T variant first detected in Lombardy, Italy, that carries a Pro323Leu amino acid substitution in NSP12, showed increased ability to activate RIPK1. Inhibition of RIPK1 downregulated the transcriptional induction of proinflammatory cytokines and host factors including ACE2 and EGFR that promote viral entry into cells. Our results suggest that SARS-CoV-2 may have an unexpected and unusual ability to hijack the RIPK1-mediated host defense response to promote its own propagation and that inhibition of RIPK1 may provide a therapeutic option for the treatment of COVID-19.

https://doi.org/10.1038/s41422-021-00578-7

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