Comparison of nonhuman primates identified the suitable model for COVID-19

Identification of a suitable nonhuman primate(NHP)model of COVID-19 remains challenging.Here,we characterized severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in three NHP species:Old World monkeys Macaca mulatta(M.mulatta)and Macaca fascicularis(M.fascicularis)and New World monkey Callithrix jacchus(C.jacchus).Infected M.mulatta and M.fascicularis showed abnormal chest radiographs,an increased body temperature and a decreased body weight.Viral genomes were detected in swab and blood samples from all animals.Viral load was detected in the pulmonary tissues of M.mulatta and M.fascicularis but not C.jacchus.Furthermore,among the three animal species,M.mulatta showed the strongest response to SARS-CoV-2,including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues.Collectively,these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M.mulatta as the most suitable for modeling COVID-19.

Low levels of neutralizing antibodies against XBB Omicron subvariants after BA.5 infection

The COVID-19 response strategies in Chinese mainland were recently adjusted due to the reduced pathogenicity and enhanced infectivity of Omicron subvariants.In Chengdu,China,an infection wave was predominantly induced by the BA.5 subvariant.It is crucial to determine whether the hybrid anti-SARS-CoV-2 immunity following BA.5 infection.

Differential Transcriptomic Landscapes of SARS-CoV-2 Variants in Multiple Organs from Infected Rhesus Macaques

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused the persistent coronavirus disease 2019(COVID-19)pandemic,which has resulted in millions of deaths worldwide and brought an enormous public health and global economic burden.The recurring global wave of infections has been exacerbated by growing variants of SARS-CoV-2.In this study,the virological characteristics of the original SARS-CoV-2 strain and its variants of concern(VOCs;including Alpha,Beta,and Delta)in vitro,as well as differential transcriptomic landscapes in multiple organs(lung,right ventricle,blood,cerebral cortex,and cerebellum)from the infected rhesus macaques,were elucidated.The original strain of SARS-CoV-2 caused a stronger innate immune response in host cells,and its VOCs markedly increased the levels of subgenomic RNAs,such as N,Orf9b,Orf6,and Orf7ab,which are known as the innate immune antagonists and the inhibitors of antiviral factors.Intriguingly,the original SARS-CoV-2 strain and Alpha variant induced larger alteration of RNA abundance in tissues of rhesus monkeys than Beta and Delta variants did.Moreover,a hyperinflammatory state and active immune response were shown in the right ventricles of rhesus monkeys by the up-regulation of inflammation-and immune-related RNAs.Furthermore,peripheral blood may mediate signaling transmission among tissues to coordinate the molecular changes in the infected individuals.Collectively,these data provide insights into the pathogenesis of COVID-19 at the early stage of infection by the original SARS-CoV-2 strain and its VOCs.

Neurological complications and infection mechanism of SARS-CoV-2

Currently,SARS-CoV-2 has caused a global pandemic and threatened many lives.Although SARS-CoV-2 mainly causes respiratory diseases,growing data indicate that SARS-CoV-2 can also invade the central nervous system(CNS)and peripheral nervous system(PNS)causing multiple neurological diseases,such as encephalitis,encephalopathy,Guillain-Barrésyndrome,meningitis,and skeletal muscular symptoms.Despite the increasing incidences of clinical neurological complications of SARS-CoV-2,the precise neuroinvasion mechanisms of SARS-CoV-2 have not been fully established.In this review,we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence.Finally,we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion.These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.

The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys

Neurological manifestations are frequently reported in the COVID-19 patients.Neuromechanism of SARS-CoV-2 remains to be elucidated.In this study,we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19.In rhesus monkey,SARS-CoV-2 invades the CNS primarily via the olfactory bulb.Thereafter,viruses rapidly spread to functional areas of the central nervous system,such as hippocampus,thalamus,and medulla oblongata.The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons,microglia,and astrocytes in the CNS.Consistently,SARS-CoV-2 infects neuro-derived SK-N-SH,glial-derived U251,and brain microvascular endothelial cells in vitro.To our knowledge,this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model,which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.

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%.

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.

SARS-CoV-2 impairs the disassembly of stress granules and promotes ALS-associated amyloid aggregation

The nucleocapsid(N)protein of SARS-CoV-2 has been reported to have a high ability of liquid-liquid phase separation,which enables its incorporation into stress granules(SGs)of host cells.However,whether SG invasion by N protein occurs in the scenario of SARS-CoV-2 infection is unknow,neither do we know its con-sequence.Here,we used SARS-CoV-2 to infect mam-malian cells and observed the incorporation of N protein into SGs,which resulted in markedly impaired self-dis-assembly but stimulated cell cellular clearance of SGs.NMR experiments further showed that N protein binds to the SG-related amyloid proteins via non-specific tran-sient interactions,which not only expedites the phase transition of these proteins to aberrant amyloid aggre-gation in vitro,but also promotes the aggregation of FUS with ALS-associated P525L mutation in cells.In addition,we found that ACE2 is not necessary for the infection of SARS-CoV-2 to mammalian cells.Our work indicates that SARS-CoV-2 infection can impair the dis-assembly of host SGs and promote the aggregation of SG-related amyloid proteins,which may lead to an increased risk of neurodegeneration.

Inactivated SARS-CoV-2 induces acute respiratory distress syndrome in human A CE2-transgenic mice

The development of animal models for COVID-19 is essential for basic research and drug/vaccine screening.Previously reported COVID-19 animal models need to be established under a high biosafety level condition for the utilization of live SARS-CoV-2,which greatly limits its application in routine research.Here,we gen erate a mouse model of COVID-19 un der a gen eral laboratory condition that captures multiple characteristics of SARS-CoV-2-induced acute respiratory distress syndrome(ARDS)observed in huma ns.Briefly,human ACE2-tra nsge nic(MCE2)mice were in tratracheally in stilled with the formaldehyde-inactivated SARS-CoV-2,resulting in a rapid weight loss and detrimental changes in lung structure and function.The pulmonary pathologic changes were characterized by diffuse alveolar damage with pulmonary consolidation,hemorrhage,necrotic debris,and hyaline membrane formation.The production of fatal cytokines(IL-β,TNF-α,and IL-6)and the infiltration of activated neutrophils,inflammatory monocyte-macrophages,and T cells in the lung were also determined,suggesting the activation of an adaptive immune response.Therapeutic strategies,such as dexamethasone or passive antibody therapy,could effectively ameliorate the disease progression in this model.Therefore,the established mouse model for SARS-CoV-2-induced ARDS in the current study may provide a robust tool for researchers in the standard open laboratory to investigate the pathological mechanisms or develop new therapeutic strategies for COVID-19 and ARDS.

Comprehensive analysis of RNA-seq and whole genome sequencing data reveals no evidence for SARS-CoV-2 integrating into host genome

Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is an RNA virus of the Coronaviridae family causing the outbreak and worldwide pandemic of coronavims disease 2019(COVID-19)(Zhou et al.,2020b;Zhu et al.,2020b).As an emergent and unprecedented global threat to public health,it has affected about 162 million individuals with over 3.3 million deaths until the middle of May.In attributed to the extensive studies on SARS-CoV-2,several kinds of vaccines are currently available which brings hope to human society for alleviating and eventually preventing COVID-19 epidemic(Zhu et al.,2020a;Xia et al.,2021).However,a better understanding of viral pathogenesis,particularly the viral-host interaction,are needed to develop effective interventions.

Proteomic and phosphoproteomic profiling of COVID-19-associated lung and liver injury:a report based on rhesus macaques

Dear Editor,The ongoing COVID-19 pandemic,caused by severe acute respiratory syndrome conronavirus 2(SARS-CoV-2),has led to over 209,201,939 confirmed cases and 4,390,467 deaths all over the world as of 19 August 2021(https://covid19.who.int/).Novel therapeutic agents and vaccines are desperately needed and mechanism exploration is imperative.Though clinical tissues are preferred samples for molecular and mechanism study,COVID-19 clinical tissues are rare and mostly come from autopsies of end-stage patients.1,2 Animal models,especially nonhuman primate models,are therefore constructed for SARS-CoV-2-associated research.