Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

Neutrophil extracellular traps (NETs) can capture and kill viruses, such as influenza viruses, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV), thus contributing to host defense. Contrary to our expectation, we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2, as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model. The histone H3 or H4 selectively binds to subunit 2 of the spike (S) protein, as shown by a biochemical binding assay, surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids. Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein. Moreover, histones enhance cell-cell fusion. Finally, treatment with an inhibitor of NETosis, histone H3 or H4, or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model. These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Weiqi Hong, Jingyun Yang, Jun Zou, Zhenfei Bi, Cai He, Hong Lei, Xuemei He, Xue Li, Aqu Alu, Wenyan Ren, Zeng Wang, Xiaohua Jiang, Kunhong Zhong, Guowen Jia, Yun Yang, Wenhai Yu, Qing Huang, Mengli Yang, Yanan Zhou, Yuan Zhao, Dexuan Kuang, Junbin Wang, Haixuan Wang, Siyuan Chen, Min Luo, Ziqi Zhang, Tianqi Lu, Li Chen, Haiying Que, Zhiyao He, Qiu Sun, Wei Wang, Guobo Shen, Guangwen Lu, Zhiwei Zhao, Li Yang, Jinliang Yang, Zhenling Wang, Jiong Li, Xiangrong Song, Lunzhi Dai, Chong Chen, Jia Geng, Maling Gou, Lu Chen, Haohao Dong, Yong Peng, Canhua Huang, Zhiyong Qian, Wei Cheng, Changfa Fan, Yuquan Wei, Zhaoming Su, Aiping Tong, Shuaiyao Lu, Xiaozhong Peng, Xiawei Wei