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HIF-1αpromotes virus replication and cytokine storm in H1N1 virus-induced severe pneumonia through cellular metabolic reprogramming

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Virologica Sinica 2024年第1期39卷 81-96页

作者： Xiaoxiao Meng Yong Zhu Wenyu Yang Jiaxiang Zhang Wei Jin Rui Tian Zhengfeng Yang Ruilan Wang Department of Critical Care Medicine Shanghai General HospitalShanghai Jiaotong UniversitySchool of MedicineShanghai201620China Precision Research Center for Refractory Diseases Shanghai General HospitalShanghai Jiaotong UniversitySchool of MedicineShanghai201620China

The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine ***,the specific mechanisms triggering virus replication and cytokine storm are still not fully ***,we identified hypoxia inducible factor-1α(HIF-1α)as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial ***,HIF-1αprotein expression is upregulated after H1N1 *** of HIF-1αattenuates pulmonary injury,viral replication and cytokine storm in *** addition,viral replication and cytokine storm were inhibited after HIF-1αknockdown in ***,the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis,with rapid production of ATP and *** of glycolysis significantly suppresses viral replication and inflammatory *** analysis revealed that H1N1-induced HIF-1αcan promote the expression of hexokinase 2(HK2),the key enzyme of glycolysis,and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate,which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/β*** conclusion,this study demonstrated that the upregulation of HIF-1αby H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2,providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.

关键词： H1N1 Severe pneumonia virus replication Hypoxia inducible factor-1α Glycolysis

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Nucleolin interacts with the rabbit hemorrhagic disease virus replicase RdRp, nonstructural proteins p16 and p23, playing a role in virus replication

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Virologica Sinica 2022年第1期37卷 48-59页

作者： Jie Zhu Qiuhong Miao Hongyuan Guo Aoxing Tang Dandan Dong Jingyu Tang Fang Wang Guangzhi Tong Guangqing Liu Shanghai Veterinary Research Institute Chinese Academy of Agricultural SciencesShanghai200241China Laboratory of Virology Wageningen University and ResearchWageningen6708 PBthe Netherlands Institute of Veterinary Medicine Jiangsu Academy of Agricultural SciencesNanjing210014China

Rabbit hemorrhagic disease virus(RHDV)is a member of the Caliciviridae family and cannot be propagated in vitro,which has impeded the progress of investigating its replication *** of an RHDV replicon system has recently provided a platform for exploring RHDV replication in host ***,aided by this replicon system and using two-step affinity purification,we purified the RHDV replicase and identified its associated host *** identified rabbit nucleolin(NCL)as a physical link,which mediating the interaction between other RNA-dependent RNA polymerase(Rd Rp)-related host proteins and the viral replicase Rd *** found that the overexpression or knockdown of NCL significantly increased or severely impaired RHDV replication in RK-13 cells,*** was identified to directly interact with RHDV Rd Rp,p16,and ***,NCL knockdown severely impaired the binding of Rd Rp to Rd Rp-related host ***,these results indicate that the host protein NCL is essential for RHDV replication and acts as a physical link between viral replicase and host proteins.

关键词： Rabbit hemorrhagic disease virus(RHDV) Nucleolin virus replication RNA-dependent RNA polymerase(RdRp)

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ISG20 inhibits bluetongue virus replication

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Virologica Sinica 2022年第4期37卷 521-530页

作者： Di Kang Shandian Gao Zhancheng Tian Guorui Zhang Guiquan Guan Guangyuan Liu Jianxun Luo Junzheng Du Hong Yin State Key Laboratory of Veterinary Etiological Biology Lanzhou Veterinary Research InstituteChinese Academy of Agricultural SciencesLanzhou730046China Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses Yangzhou UniversityYangzhou225009China

ISG20 is an interferon-inducible exonuclease that inhibits virus *** ISG20 is thought to degrade viral RNA,the antiviral mechanism and specificity of ISG20 remain *** this study,the antiviral role of ovine ISG20(o ISG20)in bluetongue virus(BTV)infection was *** was found that BTV infection upregulated the transcription of ovine ISG20(o ISG20)in a time-and BTV multiplicity of infection(MOI)-dependent *** of o ISG20 suppressed the production of BTV genome,proteins,and virus titer,whereas the knockdown of o ISG20 increased viral replication.o ISG20 was found to co-localize with BTV proteins VP4,VP5,VP6,and NS2,but only directly interacted with *** defective o ISG20 significantly decreased the inhibitory effect on BTV *** addition,the interaction of mutant o ISG20 and VP4 was weakened,suggesting that binding to VP4 was associated with the inhibition of BTV *** present data characterized the anti-BTV effect of o ISG20,and provides a novel clue for further exploring the inhibition mechanism of double-stranded RNA virus by ISG20.

关键词： Bluetongue virus(BTV) Interferon-stimulated genes(ISGs) Ovine ISG20 virus replication Antiviral immunity

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Involvement of the PI3K pathway in Largemouth Bass virus-induced apoptosis and viral replication

Involvement of the PI3K pathway in Largemouth Bass Virus-ind...

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中国水产学会鱼病专业委员会2013年学术研讨会

作者： Xiaohong Huang Wei Wang Youhua Huang Liwen Xu Shina Wei Qiwei Qin Key Laboratory of Marine Bio-resources Sustainable Utilization South China Sea Institute of OceanologyChinese Academy of Sciences South China Sea Fisheries Research Institute Chinese Academy of Fishery Sciences

Largemouth Bass Micropterus salmoides is an economically important freshwater fishcultured in *** new emerging viral diseases evoked by iridovirus and rhabdovirus havecaused great economic losses in *** better exploring the pathogenesis of LargemouthBass virus(LMBV),a ranavirus isolate,we investigated the underlying mechanism involved inviral replication and virus induced cell death in *** fluorescence microscopy and flowcytometry,we found that LMBV infection in EPC cells induced typical apoptosis,indicated as theappearance of apoptotic bodies,cytochrome C release and MMP ***,caspaseactivity detection revealed caspase-3,8 and 9 were activated with the infection time,suggestedthat not only mitochondrion-mediated,but also death receptor-mediated apoptosis were involvedin LMBV *** treatment with different inhibitors,viral gene transcription and virusproduction were significantly suppressed by the disruption of proteasome and PI3K ***,both proteasome inhibitor MG132 and PI3K inhibitor LY294002 enhanced virusinduced *** addition,LY294002 also affected the cell cycle alteration induced by ***,we speculated that proteasome system and PI3K pathway played crucial rolesin virus replication by regulated apoptosis evoked by LMBV *** together,our resultsprovided new insights into the molecular mechanism of ranavirus infection.

关键词： Largemouth Bass LMBV apoptosis proteasome PI3K pathway virus replication

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Autophagy induced by human adenovirus B7 structural protein VI inhibits viral replication

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Virologica Sinica 2023年第5期38卷 709-722页

作者： Linlin Zhang Yali Duan Wei Wang Qi Li Jiao Tian Yun Zhu Ran Wang Zhengde Xie Beijing Key Laboratory of Pediatric Respiratory Infectious Diseases Key Laboratory of Major Diseases in ChildrenMinistry of EducationNational Clinical Research Center for Respiratory DiseasesLaboratory of Infection and VirologyBeijing Pediatric Research InstituteBeijing Children's HospitalCapital Medical UniversityNational Center for Children's HealthBeijing100045China Research Unit of Critical Infection in Children 2019RU016Chinese Academy of Medical SciencesBeijing100045China Department of Infectious Diseases Beijing Children's HospitalCapital Medical UniversityNational Center for Children's HealthBeijing100045China Beijing Coal Group General Hospital Beijing100045China

Human adenovirus B7(HAdV-B7)causes severe acute lower respiratory tract infections in ***,neither the child-specific antivirals or vaccines are available,nor the pathogenesis is ***,as part of innate immunity,plays an important role in resistance to viral infection by degrading the virus and promoting the development of innate and adaptive *** study provided evidence that HAdV-B7 infection induced complete autophagic flux,and the pharmacological induction of autophagy decreased HAdV-B7 *** this process,the host protein Bcl2-associated athanogene 3(BAG3)mediated autophagy to inhibit the replication of HAdV-B7 by binding to the PPSY structural domain of viral protein pVI through its WW structural *** findings further our understanding of the host immune response during viral infection and will help to develop broad anti-HAdV therapies.

关键词： Human adenovirus B7(HAdV-B7) Autophagy Bcl2-associated athanogene 3(BAG3) virus replication

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Targeting m6A modification inhibits herpes virus 1 infection

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Genes & Diseases 2022年第4期9卷 1114-1128页

作者： Zhuoying Feng Fanghang Zhou Miaomiao Tan Tingting Wang Ying Chen Wenwen Xu Bin Li Xin Wang Xin Deng Ming-Liang He Department of Biomedical Sciences City University of Hong KongKowloonHong KongPR China MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine National Engineering Research Center of Genetic MedicineInstitute of BiomedicineCollege of Life Science and TechnologyJinan UniversityGuangzhouGuangdong 510632PR China CityU Shenzhen Research Institute ShenzhenGuangdong 518057PR China

The latent infection by herpes virus type 1(HSV-1)may be lifelong in trigeminal ganglia and a suspected cause of Alzheimer's Disease(AD)and Amyotrophic lateral sclerosis(ALS).Whether and how N6-methyladenosine(m6A)modification of viral RNAs affects virus infection are poorly ***,we report that HSV-1 infection enhanced the expression of m6A writers(METTL3,METTL14)and readers(YTHDF1/2/3)at the early infection stage and decreased their expression later on,while suppressed the erasers'(FTO,ALBKH5)expression immediately upon infection to facilitate viral *** m6A modification by 3-deazaadenosine(DAA)significantly decreased viral replication and reduced viral reproduction over 1000 *** interestingly,depleting the writers and readers by siRNAs inhibited virus replication and reproduction;whereas depleting the erasers promoted viral replication and *** YTHDF3 strikingly decreased viral replication by up to 90%,leading to reduction of up to 10-fold viral replication and over 100-fold virus reproduction,*** of m6A initiator METTL3(by 60%–70%)by siRNA correlatedly decreased viral replication 60%–70%,and reduced virus yield over ***,ectopic expression of METTL3 largely increased virus ***3 knockdown suppressed the HSV-1 intermediate early and early genes(ICP0,ICP8 and UL23)and late genes(VP16,UL44,UL49 and ICP47);while ectopic expression of METTL3 upregulated these gene *** from our study shed the lights on the importance for m6A modification to initiate HSV-1 early *** components of m6A modification machinery,particularly m6A initiator METTL3 and reader YTHDF3,would be potential important targets for combating HSV-1 infections.

关键词： Gene silencing HSV-1 infection m6A modification virus replication virus reproduction

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Recovery of a Far-Eastern Strain of Tick-Borne Encephalitis virus with a Full-Length Infectious cDNA Clone

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Virologica Sinica 2021年第6期36卷 1375-1386页

作者： Penghui Li Chen Yao Ting Wang Tong Wu Wenfu Yi Yue Zheng Yuanjiu Miao Jianhong Sun Zhongyuan Tan Yan Liu Xiaowei Zhang Hanzhong Wang Zhenhua Zheng CAS Key Laboratory of Special Pathogens and Biosafety Wuhan Institute of VirologyCenter for Biosafety MegaScienceChinese Academy of SciencesWuhan 430071China College of Life Sciences and Food Engineering Hebei University of EngineeringHandan 056038China

Tick-borne encephalitis virus(TBEV) is a pathogenic virus known to cause central nervous system(CNS) diseases in humans, and has become an increasing public health threat nowadays. The rates of TBEV infection in the endemic countries are increasing. However, there is no effective antiviral against the disease. This underscores the urgent need for tools to study the emergence and pathogenesis of TBEV and to accelerate the development of vaccines and antivirals. In this study, we reported an infectious c DNA clone of TBEV that was isolated in China(the WH2012 strain). A beta-globin intron was inserted in the coding region of nonstructural protein 1(NS1) gene to improve the stability of viral genome in bacteria. In mammalian cells, the inserted intron was excised and spliced precisely, which did not lead to the generation of inserted mutants. High titers of infectious progeny viruses were generated after the transfection of the infectious clone. The cDNA-derived TBEV replicated efficiently, and caused typical cytopathic effect(CPE) and plaques in BHK-21 cells. In addition, the CPE and growth curve of cDNA-derived virus were similar to that of its parental isolate in cells. Together, we have constructed the first infectious TBEV cDNA clone in China, and the clone can be used to investigate the genetic determinants of TBEV virulence and disease pathogenesis, and to develop countermeasures against the virus.

关键词： Tick-borne encephalitis virus(TBEV) Infectious cDNA clone Intron virus replication

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Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

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Protein & Cell 2020年第10期11卷 723-739页

作者： Rui Xiong Leike Zhang Shiliang Li Yuan Sun Minyi Ding Yong Wang Yongliang Zhao Yan Wu Weijuan Shang Xiaming Jiang Jiwei Shan Zihao Shen Yi Tong Liuxin Xu Yu Chen Yingle Liu Gang Zou Dimitri Lavillete Zhenjiang Zhao Rui Wang Lili Zhu Gengfu Xiao Ke Lan Honglin Li Ke Xu State Key Laboratory of Virology College of Life SciencesWuhan UniversityWuhan 430072China Shanghai Key Laboratory of New Drug Design State Key Laboratory of Bioreactor EngineeringSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China CAS Key Laboratory of Molecular Virology and Immunology Institut Pasteur of ShanghaiUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide,such as the on-going outbreak of the novel coronavirus ***,we identified two potent inhibitors of human DHODH,S312 and S416,with favorable drug-likeness and pharmacokinetic profiles,which all showed broad-spectrum antiviral effects against various RNA viruses,including influenza A virus,Zika virus,Ebola virus,and particularly against ***,S416 is reported to be the most potent inhibitor so far with an EC5o of 17 nmol/L and an SI value of 10,505.88 in infec-ted *** results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out *** work demonstrates that both S312/S416 and old drugs(Leflunomide/Teriflunomide)with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide,no matter such viruses are mutated or not.

关键词： de novo pyrimidine biosynthesis DHODH inhibitors SARS-CoV-2 influenza viruses virus replication immuno-regulation

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Inhibiting severe acute respiratory syndrome-associated coronavirus by small interfering RNA

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Chinese Medical Journal 2003年第8期116卷 1262-1264页

作者：张仁礼郭中敏陆家海孟锦绣周灿权詹希美黄冰余新炳黄民潘兴华凌文华陈系古万卓越郑焕英鄢心革王一飞冉延超刘新健马俊鑫王承宇张必良 Sun Yat-Sen University Center for Disease Control and Prevention of Guangdong Province Jinan University Maxim Biotech Inc. The Quartermaster University of PLA Medical School of University of Massachusetts

OBJECTIVE: To evaluate the effectiveness of small interfering RNA (siRNA) on inhibiting severe acute respiratory syndrome (SARS)-associated coronavirus replication, and to lay bases for the future clinical application of siRNA for the treatment of viral infectious diseases. METHODS: Vero-E6 cells was transfected with siRNA before SARS virus infection, and the effectiveness of siRNA interference was evaluated by observing the cytopathic effect (CPE) on Vero-E6 cells. RESULTS: Five pairs of siRNA showed ability to reduce CPE dose dependently, and two of them had the best effect. CONCLUSION: siRNA may be effective in inhibiting SARS-associated coronavirus replication.

关键词： Animals Cercopithecus aethiops RNA, Small Interfering SARS virus Transfection Vero Cells virus replication

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Diverse Regulations of Viral and Host Genes in Tomato Germplasms Responding to Tomato Yellow Leaf Curl virus Inoculation

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Agricultural Biotechnology 2023年第3期12卷 55-57,124页

作者： Wanyu XIAO Jianghua HUANG Xianyu ZHOU Hailong REN Jing ZHANG Donglin XU Guangzhou Academy of Agricultural Sciences Guangzhou 510335China College of Agriculture and Biology Zhongkai University of Agriculture and EngineeringGuangzhou 510000China

Tomato yellow leaf curl virus(TYLCV)is the dominating pathogen of tomato yellow leaf curl disease that caused severe loss to tomato production in *** this study,we found that a TYLCV-resistant tomato line drastically reduced the accumulation of viral complementary-sense strand mRNAs but just moderately inhibited that of viral DNA and virion-sense strand ***,two other resistant lines did not have such virus inhibition *** of differential expressed genes showed that the potential host defense-relevant processes varied in different resistant tomatoes,as compared to the susceptible line,suggesting a diversity of tomato TYLCV-resistance mechanisms.

关键词： Tomato yellow leaf curl virus virus replication Gene expression

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