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

作　　者：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 Tiangi 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 

机构地区：[1]Laboratory of Aging Research and Cancer Drug Targeting,State Key Laboratory of Biotherapy and Cancer Center,National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University,No.17,Block 3,Southern Renmin Road,Chengdu,Sichuan,610041,China [2]National Kunming High-level Biosafety Primate Research Center,Institute of Medical Biology,Chinese Academy of Medical Sciences and Peking Union Medical College,Yunnan,China [3]Westvac Biopharm Co.,Ltd.No.618,Fenghuang Road,Shuangliu District,Chengdu,Sichuan,China [4]Division of Animal Model Research,Institute for Laboratory Animal Resources,National Institutes for Food and Drug Control,102629,Beijing,China [5]State Key Laboratory of Medical Molecular Biology,Department of Molecular Biology and Biochemistry,Institute of Basic Medical Sciences,Medical Primate Research Center,Neuroscience Center,Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College,Beijing,China

出　　处：《Cellular & Molecular Immunology》2022年第5期577-587,共11页中国免疫学杂志（英文版）

基　　金：supported by the National Science Foundation for Excellent Young Scholars (32122052);National Natural Science Foundation Regional Innovation and Development (No.U19A2003).

摘　　要：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.

关 键 词：COVID-19 SARS-CoV-2 neutrophil extracellular traps HISTONES sialic acid 

分 类 号：R563.1[医药卫生—呼吸系统]