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 in...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Medicine R Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/13cb6a7b4ff242b7bbd1dc4b4373cfb3
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spelling	oai:doaj.org-article:13cb6a7b4ff242b7bbd1dc4b4373cfb32021-11-07T12:14:13ZSensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection10.1038/s41392-021-00800-32059-3635https://doaj.org/article/13cb6a7b4ff242b7bbd1dc4b4373cfb32021-11-01T00:00:00Zhttps://doi.org/10.1038/s41392-021-00800-3https://doaj.org/toc/2059-3635Abstract 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.Zhuo ZhouXinyi ZhangXiaobo LeiXia XiaoTao JiaoRuiyi MaXiaojing DongQi JiangWenjing WangYujin ShiTian ZhengJian RaoZichun XiangLili RenTao DengZhengfan JiangZhixun DouWensheng WeiJianwei WangNature Publishing GrouparticleMedicineRBiology (General)QH301-705.5ENSignal Transduction and Targeted Therapy, Vol 6, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Biology (General) QH301-705.5
spellingShingle	Medicine R Biology (General) QH301-705.5 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 Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection
description	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.
format	article
author	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
author_facet	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
author_sort	Zhuo Zhou
title	Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection
title_short	Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection
title_full	Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection
title_fullStr	Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection
title_full_unstemmed	Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection
title_sort	sensing of cytoplasmic chromatin by cgas activates innate immune response in sars-cov-2 infection
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/13cb6a7b4ff242b7bbd1dc4b4373cfb3
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Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection

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