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

被引：30

作者：

Hong, Weiqi ^{[1
,2
]}

Yang, Jingyun ^{[1
,2
]}

Zou, Jun ^{[1
,2
]}

Bi, Zhenfei ^{[1
,2
]}

He, Cai ^{[1
,2
]}

Lei, Hong ^{[1
,2
]}

He, Xuemei ^{[1
,2
]}

Li, Xue ^{[1
,2
]}

Alu, Aqu ^{[1
,2
]}

Ren, Wenyan ^{[1
,2
]}

Wang, Zeng ^{[1
,2
]}

Jiang, Xiaohua ^{[1
,2
]}

Zhong, Kunhong ^{[1
,2
]}

Jia, Guowen ^{[1
,2
]}

Yang, Yun ^{[3
]}

Yu, Wenhai ^{[3
]}

Huang, Qing ^{[3
]}

Yang, Mengli ^{[3
]}

Zhou, Yanan ^{[3
]}

Zhao, Yuan ^{[3
]}

Kuang, Dexuan ^{[3
]}

Wang, Junbin ^{[3
]}

Wang, Haixuan ^{[3
]}

Chen, Siyuan ^{[1
,2
]}

Luo, Min ^{[1
,2
]}

Zhang, Ziqi ^{[1
,2
]}

Lu, Tianqi ^{[1
,2
]}

Chen, Li ^{[1
,2
]}

Que, Haiying ^{[1
,2
]}

He, Zhiyao ^{[1
,2
]}

Sun, Qiu ^{[1
,2
]}

Wang, Wei ^{[1
,2
,4
]}

Shen, Guobo ^{[1
,2
,4
]}

Lu, Guangwen ^{[1
,2
,4
]}

Zhao, Zhiwei ^{[1
,2
,4
]}

Yang, Li ^{[1
,2
,4
]}

Yang, Jinliang ^{[1
,2
,4
]}

Wang, Zhenling ^{[1
,2
,4
]}

Li, Jiong ^{[1
,2
,4
]}

Song, Xiangrong ^{[1
,2
]}

Dai, Lunzhi ^{[1
,2
]}

Chen, Chong ^{[1
,2
]}

Geng, Jia ^{[1
,2
]}

Gou, Maling ^{[1
,2
]}

Chen, Lu ^{[1
,2
]}

Dong, Haohao ^{[1
,2
]}

Peng, Yong ^{[1
,2
]}

Huang, Canhua ^{[1
,2
]}

Qian, Zhiyong ^{[1
,2
]}

Cheng, Wei ^{[1
,2
]}

机构：

[1] Sichuan Univ, Lab Aging Res & Canc Drug Targeting, State Key Lab Biotherapy, Natl Clin Res Ctr Geriatr,West China Hosp, 17,Block 3,Southern Renmin Rd, Chengdu 610041, Sichuan, Peoples R China

[2] Sichuan Univ, West China Hosp, Canc Ctr, Natl Clin Res Ctr Geriatr, 17,Block 3,Southern Renmin Rd, Chengdu 610041, Sichuan, Peoples R China

[3] Chinese Acad Med Sci & Peking Union Med Coll, Inst Med Biol, Natl Kunming High Level Biosafety Primate Res Ctr, Kunming, Yunnan, Peoples R China

[4] Westvac Biopharm Co Ltd, 618 Fenghuang Rd, Chengdu, Sichuan, Peoples R China

[5] Natl Inst Food & Drug Control, Inst Lab Anim Resources, Div Anim Model Res, Beijing 102629, Peoples R China

[6] Chinese Acad Med Sci, State Key Lab Med Mol Biol, Dept Mol Biol & Biochem,Sch Basic Med,Peking Unio, Inst Basic Med Sci,Med Primate Res Ctr,Neurosci C, Beijing, Peoples R China

来源：

CELLULAR & MOLECULAR IMMUNOLOGY | 2022年 / 19卷 / 05期

基金：

美国国家科学基金会;

关键词：

COVID-19; SARS-CoV-2; neutrophil extracellular traps; histones; sialic acid; EXTRACELLULAR HISTONES; MOLECULES; DYNAMICS; MEDIATE;

D O I：

10.1038/s41423-022-00845-6

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

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.

引用

页码：577 / 587

页数：11

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