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.

Splicing factor SF3B3,a NS5-binding protein,restricts ZIKV infection by targeting GCH1

Zika virus(ZIKV),a positive-sense single-stranded RNA virus,causes congenital ZIKV syndrome in children and Guillain-Barre Syndrome(GBS)in adults.ZIKV expresses nonstructural protein 5(NS5),a large protein that is essential for viral replication.ZIKV NS5 confers the ability to evade interferon(IFN)signalling;however,the exact mechanism remains unclear.In this study,we employed affinity pull-down and liquid chromatography-tandem mass spectrometry(LC-MS/MS)analyses and found that splicing factor 3b subunit 3(SF3B3)is associated with the NS5-Flag pull-down complex through interaction with NS5.Functional assays showed that SF3B3 overexpression inhibited ZIKV replication by promoting IFN-stimulated gene(ISG)expression whereas silencing of SF3B3 inhibited expression of ISGs to promote ZIKV replication.GTP cyclohydrolase I(GCH1)is the first and ratelimiting enzyme in tetrahydrobiopterin(BH4)biosynthesis.NS5 upregulates the expression of GCH1 during ZIKV infection.And GCH1 marginally promoted ZIKV replication via the IFN pathway.Additionally,GCH1 expression is related to the regulation of SF3B3.Overexpression of the SF3B3 protein effectively reduced GCH1 protein levels,whereas SF3B3 knockdown increased its levels.These findings indicated that ZIKV NS5 binding protein SF3B3 contributed to the host immune response against ZIKV replication by modulating the expression of GCH1.

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.

Differential transcriptomic landscapes of multiple organs from SARS-CoV-2 early infected rhesus macaques

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries,how-ever,the underlying mechanism,in particular immune responses in different organs,remains elusive.In this study,comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed.Compared to normal controls,SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs,with drastic transcriptomic changes in cerebral cortex and right ventricle.Intriguingly,cerebral cortex exhibited a hyperinflammatory state evidenced by sig-nificant upregulation of inflammation response-related genes.Meanwhile,expressions of coagulation,angio-genesis and fibrosis factors were also up-regulated in cerebral cortex.Based on our findings,neuropilin 1(NRP1),a receptor of SARS-CoV-2,was significantly elevated in cerebral cortex post infection,accompanied by active immune response releasing inflammatory factors and signal transmission among tissues,which enhanced infection of the central nervous system(CNS)in a positive feedback way,leading to viral encephalitis.Overall,our study depicts a multi-tissue/organ tran-scriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2,and provides important insights into the mechanistic basis for COVID-19-asso-ciated clinical complications.

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.