This study challenges the conventional understanding of neutrophil extracellular traps (NETs) in antiviral defense. It demonstrates that histones released during NETosis, instead of inhibiting SARS-CoV-2, enhance its infectivity. This is shown through experiments using live SARS-CoV-2, pseudoviruses, and a mouse model. Histones H3 and H4 specifically bind to subunit 2 of the SARS-CoV-2 spike protein, bridging it with sialic acid on host cells. This interaction promotes cell entry and membrane fusion. Inhibiting NETosis or blocking histone binding significantly reduces viral infectivity in the mouse model. These findings suggest a novel mechanism by which SARS-CoV-2 enhances its infectivity and could be crucial in developing new COVID-19 therapies.

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