Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection.

Abstract

The global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved. Here, we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection induces the cellular level of 2'3'-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection. We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS-mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19. In addition, these findings extend our knowledge in host defense against viral infection by showing that host cells' self-nucleic acids can be employed as a "danger signal" to alarm the immune system.

• Authors: Zhuo Zhou, Xinyi Zhang, Xiaobo Lei, Xia Xiao, Tao Jiao, Ruiyi Ma, Xiaojing Dong, Qi Jiang, Wenjing Wang, Yujin Shi, Tian Zheng, Jian Rao, Zichun Xiang, Lili Ren, Tao Deng, Zhengfan Jiang, Zhixun Dou, Wensheng Wei, Jianwei Wang
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 6 Issue 1 Pg. 382 (11 03 2021) ISSN: 2059-3635 [Electronic] England
• PMID: 34732709 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Chromatin
• Nucleotidyltransferases
• cGAS protein, human
• cGAS protein, mouse

Topics

• Animals
• COVID-19 (genetics, immunology)
• Chromatin (genetics, immunology)
• Cytoplasm (genetics, immunology)
• Disease Models, Animal
• HEK293 Cells
• HeLa Cells
• Humans
• Immunity, Innate
• Mice
• Mice, Transgenic
• Nucleotidyltransferases (genetics, immunology)
• SARS-CoV-2 (genetics, immunology)