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

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Signal Transduction and Targeted Therapy 2022年第1期7卷 310-321页

作者： Zhenfei Bi Weiqi Hong Haiying Que Cai He Wenyan Ren Jingyun Yang Tianqi lu Li Chen shuaiyao lu Xiaozhong Peng Xiawei Wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityNo.17Block 3Southern Renmin RoadChengduSichuan 610041PR China National Kunming High-level Biosafety Primate Research Center Institute of Medical BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeKunmingYunnanChina

The development of animal models for COVID-19 is essential for basic research and drug/vaccine *** 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 ***,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 ***,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 *** pulmonary pathologic changes were characterized by diffuse alveolar damage with pulmonary consolidation,hemorrhage,necrotic debris,and hyaline membrane *** 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 *** strategies,such as dexamethasone or passive antibody therapy,could effectively ameliorate the disease progression in this ***,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.

关键词： distress lung routine

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

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Signal Transduction and Targeted Therapy 2021年第2期6卷 223-225页

作者： Weiqi Hong Jingyun Yang Zhenfei Bi Cai He Hong Lei Wenhai Yu Yun Yang Changfa Fan shuaiyao lu Xiaozhong Peng Xiawei Wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest Chino HospitalSichuan UniversityNo.17Block 3Southern Ren min Rood610041 ChengduSichuanPeople's Republic of China National Kunming High-level Biosafety Primate Research Center Institute of Medical BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeYun nonChina Division of Animal Model Research Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control102629 BeijingChina State Key Laboratory of Medical Molecular Biology Deportment of Molecular Biology and BiochemistryInstitute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijingChina

Dear Editor,The COVID-19 pandemic has covered more than 200 countries and regions around the world since its outbreak in January *** date,the SARS-CoV-2 virus has caused>1.2 million *** mortality rate of COVID-19 is closely concerned with the clinical symptoms of the patients from mild-to-severe ***,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%.

关键词： distress acute respiratory

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

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Protein & Cell 2022年第8期13卷 602-614页

作者： Yichen Li shuaiyao lu Jinge Gu Wencheng Xia Shengnan Zhang Shenqing Zhang Yan Wang Chong Zhang Yunpeng Sun Jian Lei Cong Liu Zhaoming Su Juntao Yang Xiaozhong Peng Dan Li Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghai 200030China School of Life Sciences and Biotechnology Shanghai Jiao Tong UniversityShanghai 200030China National Kunming High-level Biosafety Primate Research Center Institute of Medical BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeKunming 650031China State Key Laboratory of Medical Molecular Biology Chinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China State Key Laboratory of Medical Molecular Biology Department of Biochemistry and Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 201210China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Biotherapy Department of Geriatrics and National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversitChengdu 610041China Bio-X-Renji Hospital Research Center Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200240China Zhangjiang Institute for Advanced Study Shanghai Jiao Tong UniversityShanghai 200240China

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 ***,whether SG invasion by N protein occurs in the scenario of SARS-CoV-2 infection is unknow,neither do we know its ***,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 *** 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 *** addition,we found that ACE2 is not necessary for the infection of SARS-CoV-2 to mammalian *** 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.

关键词： SARS-CoV-2 nucleocapsid protein stress granule

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

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Signal Transduction and Targeted Therapy 2023年第7期8卷 3486-3497页

作者： Jingyun Yang Weiqi Hong Hong Lei Cai He Wenwen Lei Yanan Zhou Tingmei Zhao Aqu Alu Xuelei Ma Jiong Li Li Yang Zhenling Wang Wei Wang Guangwen lu Guobo Shen shuaiyao lu Guizhen Wu Huashan Shi Xiawei Wei Laboratory of Aging Research and Cancer Drug Target Department of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityNo.17Block 3Southern Renmin RoadChengduSichuan 610041People’s Republic of China NHC Key Laboratory of Biosafety National Institute for Viral Disease Control and PreventionChinese Center for Disease Control and Prevention(China CDC)Beijing 102206China National Kunming High-level Biosafety Primate Research Center Institute of Medical BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeKunmingYunnanChina

The COVID-19 response strategies in Chinese mainland were recently adjusted due to the reduced pathogenicity and enhanced infectivity of Omicron *** Chengdu,China,an infection wave was predominantly induced by the BA.... 详细信息

关键词： immunity infection antibodies

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

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Genomics, Proteomics & Bioinformatics 2023年第5期21卷 1014-1029页

作者： Tingfu Du Chunchun Gao shuaiyao lu Qianlan Liu Yun Yang Wenhai Yu Wenjie Li Yong Qiao Sun Cong Tang Junbin Wang Jiahong Gao Yong Zhang Fangyu luo Ying Yang Yun-Gui Yang Xiaozhong Peng National Kunming High-level Biosafety Primate Research Center Institute of Medical BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeKunming 650118China State Key Laboratory of Medical Molecular Biology Department of Molecular Biology and BiochemistryInstitute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China CAS Key Laboratory of Genomic and Precision Medicine Collaborative Innovation Center of Genetics and DevelopmentCollege of Future TechnologyBeijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China Sino-Danish College University of Chinese Academy of SciencesBeijing 100049China Institute of Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Institute of Laboratory Animal Science Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

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 *** recurring global wave of infections has been exacerbated by growing variants of *** 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 *** 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 ***,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 ***,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 ***,peripheral blood may mediate signaling transmission among tissues to coordinate the molecular changes in the infected ***,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.

关键词： SARS-CoV-2 Variant of concern Subgenomic RNA Rhesus macaque Transcriptome

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

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Virologica Sinica 2023年第2期38卷 222-232页

作者： Tanxiu Chen Hao Yang Penghui Liu Moliduer Hamiti Xintian Zhang Yi Xu Wenqi Quan Yong Zhang Wenhai Yu Li Jiao Tingfu Du Juemin Xi Bin Yin Wei Zhou shuaiyao lu Xiaozhong Peng Institute of Medical Biology Chinese Academy of Medical Sciences and Peking Union Medical CollegeKunming650031China Department of Science and Education Jiangxi Key Laboratory of Translational Cancer ResearchJiangxi Cancer HospitalNanchang330029China The State Key Laboratory of Medical Molecular Biology Department of Molecular Biology and BiochemistryInstitute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100730China

Zika virus(ZIKV),a positive-sense single-stranded RNA virus,causes congenital ZIKV syndrome in children and Guillain-Barre Syndrome(GBS)in *** expresses nonstructural protein 5(NS5),a large protein that is essential for viral *** NS5 confers the ability to evade interferon(IFN)signalling;however,the exact mechanism remains *** 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 *** 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 *** cyclohydrolase I(GCH1)is the first and ratelimiting enzyme in tetrahydrobiopterin(BH4)***5 upregulates the expression of GCH1 during ZIKV *** GCH1 marginally promoted ZIKV replication via the IFN ***,GCH1 expression is related to the regulation of *** of the SF3B3 protein effectively reduced GCH1 protein levels,whereas SF3B3 knockdown increased its *** findings indicated that ZIKV NS5 binding protein SF3B3 contributed to the host immune response against ZIKV replication by modulating the expression of GCH1.

关键词： Nonstructural protein 5(NS5) Splicing factor 3b subunit 3(SF3B3) GTP cyclohydrolase I(GCH1) IFN-stimulated gene(ISGs) IFN signalling Pathway

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

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Protein & Cell 2022年第5期13卷 379-385页

作者： Yu-Sheng Chen shuaiyao lu Bing Zhang Tingfu Du Wen-Jie Li Meng Lei Yanan Zhou Yong Zhang Penghui Liu Yong-Qiao Sun Yong-Liang Zhao Ying Yang Xiaozhong Peng Yun-Gui Yang CAS Key Laboratory of Genomic and Precision Medicine Collaborative Innovation Center of Genetics and DevelopmentCollege of Future TechnologyBeijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National Center for Bioinformation Beijing 100101China National Kunming High-level Biosafety Primate Research Center Institute of Medical BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeKunming 650031China Institute of Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Medical Molecular Biology Department of Molecular Biology and BiochemistryInstitute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic Medicine PekingUnion Medical CollegeBeijing 100005China

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 *** 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.

关键词： integrating eventually attributed

Orally administered BZL-s RNA-20 oligonucleotide targeting TLR4 effectively ameliorates acute lung injury in mice

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Science China(Life Sciences) 2023年第7期66卷 1589-1599页

作者： Dandan Zhao Yuhao Qin Jiaqi Liu Kegong Tang shuaiyao lu Zirui Liu Yexuan Lin Cong Zhang Fengming Huang Jiahui Chang Chang Li Mingyao Tian Yiming Ma Xiaoyun Li Congzhao Zhou Xiao Li Xiaozhong Peng Ningyi Jin Chengyu Jiang State Key Laboratory of Medical Molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical SciencesDepartment of BiochemistryPeking Union Medical CollegeBeijing 100005China Institute of Medical Biology Chinese Academy of Medical SciencesKunming 650031China Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences University of Science and Technology of ChinaHefei 230027China Changchun Veterinary Research Institute Chinese Academy of Agricultural SciencesChangchun 130122China

The global COVID-19 pandemic emerged at the end of December *** respiratory distress syndrome(ARDS)and acute lung injury(ALI)are common lethal outcomes of bacterial lipopolysaccharide(LPS),avian influenza virus,and SARS-Co ***-like receptor 4(TLR4)is a key target in the pathological pathway of ARDS and *** studies have reported that herbal small RNAs(s RNAs)are a functional medical ***-s RNA-20(Accession number:B59471456;Family ID:F2201.Q001979.B11)is a potent inhibitor of Toll-like receptor 4(TLR4)and pro-inflammatory ***,BZLs RNA-20 reduces intracellular levels of cytokines induced by lipoteichoic acid(LTA)and polyinosinic-polycytidylic acid(poly(I:C)).We found that BZL-s RNA-20 rescued the viability of cells infected with avian influenza H5N1,SARS-Co V-2,and several of its variants of concern(VOCs).Acute lung injury induced by LPS and SARS-Co V-2 in mice was significantly ameliorated by the oral medical decoctosome mimic(bencaosome;sphinganine(d22:0)+BZL-s RNA-20).Our findings suggest that BZLs RNA-20 could be a pan-anti-ARDS/ALI drug.

关键词： oligonucleotide drug herbal medicine ARDS/ALI SARS-CoV-2

Immunogenicity and protective efficacy of a recombinant protein subunit vaccine and an inactivated vaccine against SARS-CoV-2 variants in non-human primates

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Signal Transduction and Targeted Therapy 2022年第4期7卷 1170-1180页

作者： Qian He Qunying Mao Xiaozhong Peng Zhanlong He shuaiyao lu Jialu Zhang Fan Gao Lianlian Bian Chaoqiang An Wenhai Yu Fengmei Yang Yanan Zhou Yun Yang Yanyan Li Yadi Yuan Xujia Yan Jinghuan Yang Xing Wu Weijin Huang Changgui Li Junzhi Wang Zhenglun Liang Miao Xu Division of Hepatitis and Enterovirus Vaccines Institute of Biological ProductsNational Institutes for Food and Drug ControlNHC Key Laboratory of Research on Quality and Standardization of Biotech ProductsNMPA Key Laboratory for Quality Research and Evaluation of Biological ProductsBeijing 102629People’s Republic of China Institute of Medical Biology Chinese Academy of Medicine Sciences&Peking Union Medical CollegeKunming 650118People’s Republic of China

Emerging SARS-CoV-2 variants and the gradually decreasing neutralizing antibodies over time post vaccination have led to an increase in incidents of breakthrough infection across the *** investigate the potential protective effect of the recombinant protein subunit COVID-19 vaccine targeting receptor-binding domain(RBD)(PS-RBD)and whole inactivated virus particle vaccine(IV)against the variant strains,in this study,rhesus macaques were immunized with PS-RBD or IV vaccine,followed by a Beta variant(B.1.351)*** neutralizing activity against the Beta variant was reduced compared with that against the prototype,the decreased viral load in both upper and lower respiratory tracts,milder pathological changes,and downregulated inflammatory cytokine levels in lung tissues after challenge demonstrated that PS-RBD and IV still provided effective protection against the Beta variant in the macaque ***,PS-RBD-induced macaque sera possessed general binding and neutralizing activity to Alpha,Beta,Delta,and Omicron variants in our study,though the neutralizing antibody(NAb)titers declined by varying degrees,demonstrating potential protection of PS-RBD against current circulating variants of concern(VOCs).Interestingly,although the IV vaccine-induced extremely low neutralizing antibody titers against the Beta variant,it still showed reduction for viral load and significantly alleviated pathological *** correlates of vaccine-induced protection(CoP)like antibody-dependent cellular cytotoxicity(ADCC)and immune memory were both confirmed to be existing in IV vaccinated group and possibly be involved in the protective mechanism.

关键词： protective vaccine neutral