Xiaopeng Wan,Jiqing Li,Yupeng Wang,Xiaofei Yu,Xijun He,Jianzhong Shi,Guohua Deng,Xianying Zeng,Guobin Tian,Yanbing Li,Yongping Jiang,Yuntao Guan,Chengjun Li,Feng Shao,Hualan Chen

Natl Sci Rev. 2021 Jul 30;9(1):nwab137.doi: 10.1093/nsr/nwab137.eCollection 2022 Jan

Abstract

The H7N9 influenza virus emerged in China in 2013, causing more than 1560 human infections, 39% of which were fatal. A 'cytokine storm' in the lungs of H7N9 patients has been linked to a poor prognosis and death; however, the underlying mechanism that triggers the cytokine storm is unknown. Here, we found that efficient replication of the H7N9 virus in mouse lungs activates gasdermin E (GSDME)-mediated pyroptosis in alveolar epithelial cells, and that the released cytosolic contents then trigger a cytokine storm. Knockout of  Gsdme  switched the manner of death of A549 and human primary alveolar epithelial cells from pyroptosis to apoptosis upon H7N9 virus infection, and  Gsdme  knockout mice survived H7N9 virus lethal infection. Our findings reveal that GSDME activation is a key and unique mechanism for the pulmonary cytokine storm and lethal outcome of H7N9 virus infection and thus opens a new door for the development of antivirals against the H7N9 virus.

Keywords: H7N9 virus; cytokine storm; gasdermin E; pyroptosis.