Abstract
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.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes an infectious viral respiratory disease known as COVID-19, severely affecting global public health year-round
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
Treatment with PMA or Cl-amidine alone did not cause cytopathogenic effects (Fig. 1A). These findings indicate that the increased infectivity of SARS-CoV-2 may be related to neutrophil NETosis
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes an infectious viral respiratory disease known as COVID-19, severely affecting global public health year-round. The four structural proteins of SARS-CoV-2 are the spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins [1]. The S protein of SARS-CoV-2 consists of two subunits, S1 and S2, which are responsible for receptor recognition and the cell membrane fusion process, respectively [2]. SARS-CoV-2 first binds to the ACE2 receptor on the host cell surface via the virion RBD in S1. Research on the high neutralization potency of human monoclonal antibodies that bind to the SARS-CoV-2 S protein but do not bind RBD suggested the existence of other (co)receptors or mechanisms for the entry of SARSCoV-2 into cells [4]. Recent studies revealed that S1 of SARS-CoV-2 could bind to other receptors or coreceptors, such as neuropilin, heparan sulfate, HDL-scavenger receptor B type 1 (SR-B1), tyrosineprotein kinase receptor UFO (AXL) and CD147, to facilitate cell entry and potentiate infectivity [5–10]. No reports indicate that S2 of SARS-CoV-2 can interact with host factors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
