Volume 33, No 3, Mar 2023

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

Volume 33 Issue 3, March 2023: 201-214

ORIGINAL ARTICLES

SARS-CoV-2 Z-RNA activates the ZBP1-RIPK3 pathway to promote virus-induced inflammatory responses

Shufen Li^1,† , Yulan Zhang^1,† , Zhenqiong Guan^1,2,† , Meidi Ye^1,2 , Huiling Li^1,2 , Miaomiao You^1,2 , Zhenxing Zhou³ , Chongtao Zhang¹ , Fan Zhang¹ , Ben Lu^4,* , Peng Zhou^5,* , Ke Peng^1,2,6,*

¹State Key Laboratory of Virology, Center for Antiviral Research, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
²University of Chinese Academy of Sciences, Beijing, China
³University of Science and Technology of China, Hefei, Anhui, China
⁴Department of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan, China
⁵Guangzhou Laboratory, Guangzhou, Guangdong, China
⁶Hubei Jiangxia Laboratory, Wuhan, Hubei, China
^†These authors contributed equally: Shufen Li, Yulan Zhang, Zhenqiong Guan
Correspondence: Ben Lu(xybenlu@csu.edu.cn)Peng Zhou(zhou_peng@gzlab.ac.cn)Ke Peng(pengke@wh.iov.cn)

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.

https://doi.org/10.1038/s41422-022-00775-y

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