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

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.

A mouse model for SARS-CoV-2-induced acute respiratory distress syndrome

Dear Editor,The COVID-19 pandemic has covered more than 200 countries and regions around the world since its outbreak in January 2020.To date,the SARS-CoV-2 virus has caused>1.2 million deaths.The mortality rate of COVID-19 is closely concerned with the clinical symptoms of the patients from mild-to-severe disease.Notably,in its most severe form,COVID-19 leads to life-threatening pneumonia and acute respiratory distress syndrome(ARDS),which is mostly accom-panied by a hyperactive immune response called"cytokine storm"and has high death rates from 40 to 50%.

The Infection and Pathogenicity of SARS-CoV-2 Variant B.1.351 in hACE2 Mice

Dear Editor,Since the outbreak of COVID-19 at the end of 2019,its causative agent SARS-Co V-2 has been spreading around the world for one and half a year.During the long global circulation of SARS-Co V-2,mutations in the viral genome gradually emerged and accumulated。

Animal models for COVID-19:advances,gaps and perspectives

COVID-19,caused by SARS-CoV-2,is the most consequential pandemic of this century.Since the outbreak in late 2019,animal models have been playing crucial roles in aiding the rapid development of vaccines/drugs for prevention and therapy,as well as understanding the pathogenesis of SARS-CoV-2 infection and immune responses of hosts.However,the current animal models have some deficits and there is an urgent need for novel models to evaluate the virulence of variants of concerns(VOC),antibodydependent enhancement(ADE),and various comorbidities of COVID-19.This review summarizes the clinical features of COVID-19 in different populations,and the characteristics of the major animal models of SARS-CoV-2,including those naturally susceptible animals,such as non-human primates,Syrian hamster,ferret,minks,poultry,livestock,and mouse models sensitized by genetically modified,AAV/adenoviral transduced,mouse-adapted strain of SARS-CoV-2,and by engraftment of human tissues or cells.Since understanding the host receptors and proteases is essential for designing advanced genetically modified animal models,successful studies on receptors and proteases are also reviewed.Several improved alternatives for future mouse models are proposed,including the reselection of alternative receptor genes or multiple gene combinations,the use of transgenic or knock-in method,and different strains for establishing the next generation of genetically modified mice.