Journal Article

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

Zhao, Ping, Zhang, Shengyuan, Qu, Jing, Li, Dekang, Tong, Yilun, Liu, Liang, Wu, Guowei, Wang, Yunyun, Qi, Chunting, Liu, Yang, Dong, Kangyun, Jin, Taijie, Li, Ying, Peng, Haoran, Zhang, Zheng, Li, Liang, Xiao, Tongyang, Yuan, Junying, Gou, Jizhou, Xu, Gang, He, Zhuohao

2021

Overview

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.

• Publisher: Springer Singapore,Nature Publishing Group
• Subject: 631/80 / 631/80/304 / ACE2 / Amino acid substitution / Amino acids / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - genetics / Animals / Biomedical and Life Sciences / Cell Biology / Cell death / Coronavirus RNA-Dependent RNA Polymerase - genetics / Coronavirus RNA-Dependent RNA Polymerase - metabolism / Coronaviruses / COVID-19 / COVID-19 - drug therapy / COVID-19 - mortality / COVID-19 - pathology / COVID-19 - virology / Cytokine storm / Cytokines / Cytokines - genetics / Cytokines - metabolism / DNA-directed RNA polymerase / Down-Regulation - drug effects / ErbB Receptors - metabolism / Humans / Imidazoles - pharmacology / Imidazoles - therapeutic use / Indoles - pharmacology / Indoles - therapeutic use / Inflammation / Inflammatory response / Innate immunity / Kinases / Life Sciences / Lung - pathology / Lung - virology / Lungs / Mice / Mice, Transgenic / Mutation / Organoids / Pandemics / Protein kinase / Public health / Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / RNA polymerase / RNA-directed RNA polymerase / SARS-CoV-2 - isolation & purification / SARS-CoV-2 - metabolism / SARS-CoV-2 - physiology / Severe acute respiratory syndrome coronavirus 2 / Survival Rate / Threonine / Transcription activation / Transcriptome - drug effects / Transgenic animals / Transgenic mice / Viral diseases / Viral Load - drug effects / Virus Internalization