Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells.
Weiqi HongJingyun YangJun ZouZhenfei BiCai HeHong LeiXuemei HeXue LiAqu AluWenyan RenZeng WangXiaohua JiangKunhong ZhongGuowen JiaYun YangWenhai YuQing HuangMengli YangYanan ZhouYuan ZhaoDexuan KuangJunbin WangHaixuan WangSiyuan ChenMin LuoZiqi ZhangTianqi LuLi ChenHaiying QueZhiyao HeQiu SunWei WangGuobo ShenGuangwen LuZhiwei ZhaoLi YangJinliang YangZhenling WangJiong LiXiangrong SongLunzhi DaiChong ChenJia GengMaling GouLu ChenHaohao DongYong PengCanhua HuangZhiyong QianWei ChengChangfa FanYuquan WeiZhaoming SuAiping TongShuai-Yao LuXiaozhong PengYanping QianPublished in: Cellular & molecular immunology (2022)
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.
Keyphrases
- sars cov
- human immunodeficiency virus
- amino acid
- mouse model
- respiratory syndrome coronavirus
- cell surface
- respiratory syncytial virus
- single cell
- antiretroviral therapy
- hepatitis c virus
- induced apoptosis
- binding protein
- protein protein
- hiv infected
- cell therapy
- coronavirus disease
- hiv positive
- cell death
- oxidative stress
- stem cells
- small molecule
- high throughput
- protein kinase
- ionic liquid
- endoplasmic reticulum stress
- respiratory tract