Abstract
SARS-CoV-2 infection can trigger strong inflammatory responses and cause severe lung damage in COVID-19 patients with critical illness. However, the molecular mechanisms by which the infection induces excessive inflammatory responses are not fully understood. Here, we report that SARS-CoV-2 infection results in the formation of viral Z-RNA in the cytoplasm of infected cells and thereby activates the ZBP1-RIPK3 pathway. Pharmacological inhibition of RIPK3 by GSK872 or genetic deletion of MLKL reduced SARS-CoV-2-induced IL-1β release. ZBP1 or RIPK3 deficiency leads to reduced production of both inflammatory cytokines and chemokines during SARS-CoV-2 infection both in vitro and in vivo. Furthermore, deletion of ZBP1 or RIPK3 alleviated SARS-CoV-2 infection-induced immune cell infiltration and lung damage in infected mouse models. These results suggest that the ZBP1-RIPK3 pathway plays a critical role in SARS-CoV-2-induced inflammatory responses and lung damage. Our study provides novel insights into how SARS-CoV-2 infection triggers inflammatory responses and lung pathology, and implicates the therapeutic potential of targeting ZBP1-RIPK3 axis in treating COVID-19.
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Acknowledgements
This work was supported by the National Key R&D Program of China (2018YFA0507201, 2021YFC2300702, 2022YFC2303302), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29010204), Creative Research Group Program of Natural Science Foundation of Hubei Province (2022CFA021), the National Natural Science Foundation of China (32070179), Self-supporting Program of Guangzhou Laboratory (SRPG22-001), the Hundred Talents Program of Chinese Academy of Sciences (to Ke Peng), and the Advanced Customer Cultivation Project of Wuhan National Biosafety Laboratory, Chinese Academy of Sciences (2022ACCP-MS10). We would like to thank Dr Ding Gao, Ms Anna Du and Ms Juan Min, from the Center for Instrumental Analysis and Metrology, Wuhan Institute of Virology, Chinese Academy of Science for technical assistance. We would like to acknowledge Ms Xuefang An, Mr He Zhao, Ms Li Li and Ms Youling Zhu from the Center for Experimental Animals, Wuhan Institute of Virology for help in animal experiments. We thank Tao Du, Jia Wu, Hao Tang and Jun Liu from the BSL-3 Laboratory, Wuhan Institute of Virology for their essential support.
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K.P., P.Z. and B.L. conceived and supervised the study. K.P., P.Z., B.L., S.L., Y.Z. and Z.G. participated in the study design, analyzed the data, and wrote the manuscript. S.L., Y.Z., Z.G., M.D.Y., H.L., M.M.Y., C.Z. and Z.Z. performed the experiments. All authors read and approved the manuscript.
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Li, S., Zhang, Y., Guan, Z. et al. SARS-CoV-2 Z-RNA activates the ZBP1-RIPK3 pathway to promote virus-induced inflammatory responses. Cell Res 33, 201–214 (2023). https://doi.org/10.1038/s41422-022-00775-y
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DOI: https://doi.org/10.1038/s41422-022-00775-y
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