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

  • Cell Res. 2023 Jan 17;1-14. doi: 10.1038/s41422-022-00775-y.
Shufen Li  #  1 ,  Yulan Zhang  #  1 ,  Zhenqiong Guan  #  1  2 ,  Meidi Ye  1  2 ,  Huiling Li  1  2 ,  Miaomiao You  1  2 ,  Zhenxing Zhou  3 ,  Chongtao Zhang  1 ,  Fan Zhang  1 ,  Ben Lu  4 ,  Peng Zhou  5 ,  Ke Peng  6  7  8
Affiliations
  • 1. State Key Laboratory of Virology, Center for Antiviral Research, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China.
  • 2. University of Chinese Academy of Sciences, Beijing, China.
  • 3. University of Science and Technology of China, Hefei, Anhui, China.
  • 4. Department of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
  • 5. Guangzhou Laboratory, Guangzhou, Guangdong, China. [email protected].
  • 6. State Key Laboratory of Virology, Center for Antiviral Research, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China. [email protected].
  • 7. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 8. Hubei Jiangxia Laboratory, Wuhan, Hubei, China. [email protected].
  • # Contributed equally.
PMID: 36650286 DOI: 10.1038/s41422-022-00775-y
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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