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创新研究群体项目获得者

王祥喜  博士 研究员 博士生导师  

中科院生物物理所,中科院感染与免疫重点实验室,研究组长

研究方向:病毒入侵、复制与组装分子机制

电子邮件:xiangxi@ibp.ac.cn

电       话:010-64888806

通讯地址:北京市朝阳区大屯路15号(100101)

英文版个人网页:http://english.ibp.cas.cn/faculty/index_18316.html?json=http://www.ibp.cas.cn/sourcedb_ibp_cas/cn/ibpexport/EN_xsszmW/202005/t20200519_5582974.json

 

简       历:

  2009  四川大学生物技术专业,获得理学学士学位

  2014  中国科学院生物物理研究所,获得理学博士学位

  2014.07 - 2014.09  中国科学院生物物理研究所,副研究员

  2014.09 - 2016.02  牛津大学,访问学者

  2014.10 - 至今       中国科学院生物物理研究所,研究员

获奖及荣誉:

  2014年  吴瑞奖学金

  2014年  中国科学院青年研究员人才计划

  2015年  青年人才托举工程

  2015年  贝时璋青年生物物理学家奖

  2020年  中国科学院青年科学家奖

  2020年  中源协和生命医学创新奖

社会任职:

 

研究方向:

  运用低温冷冻电镜、病毒学、细胞生物学等技术方法,从事人类重大疾病直接相关的病毒完整颗粒及病毒与受体、病毒与抗体的超大分子复合物的精细三维结构和相关功能研究,揭示病毒入侵宿主细胞的分子机制和致病机理以及抗病毒药物研究。主要研究方向包括:1.疱疹病毒的复制、组装和运输机制;2.脑炎性黄病毒神经毒力的分子机制;3.非洲猪瘟病毒、新型冠状病毒的免疫机制与疫苗设计。

  1. 疱疹病毒的复制、组装和运输机制

  疱疹病毒是在世界范围内广泛传播的一大类病毒,包含病毒的种类众多,能够感染包括人类在内的多种哺乳动物。疱疹病毒在感染人体后能够引发多种疾病,包括口腔和生殖器疱疹、水痘、带状疱疹,严重的甚至包括多种免疫系统疾病、脑炎以及癌症等。疱疹病毒有着独特的潜伏-再活化机制,疱疹病毒可以关闭其大部分活动状态的基因,只在特定的潜伏阶段打开特定的少数基因,并在合适的条件下恢复活性,重新进入增殖过程。这种潜伏-再活化机制使得疱疹病毒感染产生的疾病难以完全治愈,通常患者会终生携带病毒。同时疱疹病毒又是非常好的“融瘤”和“神经环路示踪”工具,目前已经进入临床应用。本课题组致力于理解疱疹病毒的复制、组装的动态过程,揭示疱疹病毒在宿主细胞的运输和潜伏与再激活分子机理,为有效防治疱疹病毒的感染和人类生命医学技术手段的提高提供理论基础。  

  2. 脑炎性黄病毒神经毒力的分子机制

  黄病毒,是一类具有包膜的单股正链RNA病毒,主要是通过吸血的节肢动物(蚊、蜱、白蛉等) 进行传播的虫媒病毒,能够广泛引起人类很多重大传染性疾病,主要包括乙型脑炎病毒 (JEV)、森林脑炎病毒、登革热病毒、寨卡病毒和黄热病毒等。黄病毒科中有一大类病毒能够直接入侵脑部而引起的颅内急性炎症,即:病毒性脑炎。本课题组聚焦脑炎性黄病毒神经毒力的分子机制。

  3. 非洲猪瘟病毒、新型冠状病毒免疫机制及疫苗设计;

  疫苗主要通过免疫原和佐剂诱发机体体液与细胞免疫反应,产生中和性抗体等保护物质,当机体再次接触到这种病原体时,机体快速启动其免疫系统进行中和、杀伤病原体。传统的疫苗包括减毒活疫苗、灭活疫苗、载体疫苗、亚单位疫苗等,能够有效保护多种传染性疾病,然而对于某些传染病,如:艾滋、登革热、呼吸道合胞体病毒肺炎等无效。新技术路线的疫苗,如:mRNA疫苗、纳米颗粒候选疫苗等展现出研发周期短,快速、高效诱导、长期保护、个性化升级等优势,具有前景。新型疫苗研发的核心在于设计理念,建立在一定的基础研究上,在体内或体外表达出稳定且构象正确的免疫原,诱导出充足量的中和性抗体。最佳的免疫是产生多种不同类别的中和性抗体(中和抗体多样性),靶向不同的表位,采用不同的中和机制而发挥其高效抑制作用,还能抵抗病毒局部位点突变引发疫苗失效的风险。然而未经设计的免疫原只能诱导出部分中和性抗体,尤其是记忆性抗体比例更低。系统性研究多种中和性抗体的识别表位、中和效价、中和机制、记忆性关联及母系生成机制等科学问题,基于其结构特征、免疫特性等反向、靶向改造免疫原,将关键特异性(或广谱性)抗原表位、记忆性及T细胞杀伤表位等信号进行逐级放大增强,屏蔽或大幅度降低无效的机体免疫反应,提高机体“精准”免疫应答的效率,进而产生广谱、高效且长期的保护。为探索精准疫苗学提供新理论。

承担项目情况:

 

代表论著:

2021年度

  1. Guo Q.#, Zhao Y.#, Li J.#, Liu J.#, Yang X.#, Guo X., Kuang M., Xia H., Zhang Z., Cao L., Luo Y., Bao L., Wei X., Deng W., Wang N., Chen L., Chen J., Zhu H., Gao R., Qin, C.*, Wang X.*, You F.*, Induction of alarmin S100A8/A9 mediates activation of aberrant neutrophils in the pathogenesis of COVID-19, Cell Host and Microbe, 2021, https://doi.org/10.1016/ j.chom.2020.12.016.

  2. Zhu L#, Deng Y#, Zhang R#, Cui Z#, Sun C#, Fan C#, Xing X#, Huang W, Chen Q, Zhang N, Ye, Q, Cao T, Wang N, Wang L, Cao L, Wang H, Kong D, Ma J, Luo C, Zhang Y, Nie J, Sun Y, Lv Z, Shaw N, Li Q, Li X, Hu J, Xie L*, Rao Z*, Wang Y*, Wang X*, Qin C*, Double lock of a potent human therapeutic monoclonal antibody against SARS-CoV-2, National Science Review, 2021, nwaa297

  3. Dong H.#, Liu P.#, Bai M.#, Wang K.#, Feng R.#, Zhu D., Sun Y., Mu S., Li H., Michiel H., Sun, S.*, Wang X.*, Guo H.*,Structural and molecular basis for foot-and-mouth disease virus neutralization by two potent protective antibodies, Protein and Cell, 2021 (In press)

2020年度

  4. Yao H#, Sun Y#, Deng Y#, Wang N#, Tan Y#, Zhang N#, Li X, Kong C, Xu Y, Chen Q, Cao T, Zhao H, Yan X, Cao L, Lv Z, Zhu D, Feng R, Wu N, Zhang W, Hu Y, Chen K, Zhang R, Lv Q, Sun S, Zhou Y, Yan R, Yang G, Sun X, Liu C, Lu X, Cheng L, Qiu H, Huang X, Weng T, Shi D, Jiang W, Shao J, Wang L, Zhang J, Jiang T, Lang G*, Qin C*, Li L*, Wang X*. Rational Development of a Human Antibody Cocktail that Deploys Multiple Functions to Confer Pan-SARS-CoVs Protection, Cell Research, 2020, 10.1038/s41422-020-00444-y

  5. Wang N#, Sun Y#, Feng R#, Wang Y#, Guo Y#, Zhang L#, Deng Y, Wang L, Cui Z, Cao L, Zhang Y, Li W*, Zhu F*, Qin C*, Wang X*. Structure-based development of human antibody cocktails against SARS-CoV-2, Cell Research, 2020, 10.1038/s41422-020-00446-w

  6. Zhang Y#, Zeng G#, Pan H#, Li C#, Hu Y, Chu K, Han W, Chen Z, Tang R, Yin W, Chen X, Hu Y, Liu X, Jiang C, Li J, Yang M, Song Y, Wang X, Gao Q*, Zhu F*, Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial, The Lancet Infectious Diseases, 2020, 10.1016/ S1473-3099(20)30870-7

  7. Lv Z#, Deng Y#, Ye Q#, Cao L#, Sun C#, Fan C#, Huang W, Sun S, Sun Y, Zhu L, Chen Q, Wang N, Nie J, Cui Z, Zhu D, Shaw N, Li X, Li Q, Xie L*, Wang Y*, Rao Z*, Qin C*, Wang X*, Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody, Science, 2020, 369(6510):1505-1509

  8. Gao Q#, Bao L#, Mao H#, Wang L#, Xu K#, Yang M#, Li Y, Zhu L, Wang N, Zhe Lv, Gao H, Ge X, Kan B, Hu Y, Liu J, Cai F, Jiang D, Yin Y, Qin C, Li J, Gong X, Lou X, Shi W, Wu D, Zhang H, Zhu L, Deng W, Li Y, Lu J*, Li C*, Wang X*, Yin W*, Zhang Y*, Qin Q*,Development of an inactivated vaccine candidate for SARS-CoV-2, Science, 2020,369(6499):77-81

  9. Wang K#, Zhu L#, Sun Y#, Li M, Zhao X, Cui L, Zhang L, George F. Gao, Zhai W, Zhu F*, Rao Z, Wang X*, Structures of Echovirus 30 in complex with its receptors inform a rational prediction for enterovirus receptor usage. Nature Communications 11, 4421 (2020).

  10. Wang K#, Zheng B#, Zhang L#, Cui L, Su X, Zhang Q, Guo Z, Guo Y, Zhang W, Zhu L*, Zhu F*, Rao Z*, Wang X*, Serotype specific epitopes identified by neutralizing antibodies underpin immunogenic differences in Enterovirus B. Nature Communications 11, 4419 (2020)

  11. Yang Y#, Yang P#, Wang N, Chen Z, Su D, Zhou ZH, Rao Z*, Wang X*, Architecture of the herpesvirus genome-packaging complex and implications for DNA translocation, Protein & Cell 11, 339-351 (2020).

  12. Wang N#, Chen W#, Zhu L#, Zhu D, Feng R, Wang J, Zhu B, Zhang X, Chen X, Liu X, Yan R, Ni D, Grace Zhou G, Liu H*, Rao Z*, Wang X*, Structures of the portal vertex reveal essential protein-protein interactions for Herpesvirus assembly and maturation. Protein & Cell 11, 366-373 (2020)

  13. Zhang M, Wang Y, He W, Sun Y, Guo Y, Zhong W, Gao Q, Liao M, Wang X, Cai Y*, Guo Y*, and Rao Z,Design, Synthesis, and Evaluation of Novel Enterovirus 71 Inhibitors as Therapeutic Drug Leads for the Treatment of Human Hand, Foot, and Mouth Disease,J. Med. Chem. 2020, 63, 3, 1233-1244

  14. Zhao Y, Zhou D, Ni T, Karia D, Kotecha A, Wang X, Rao Z, Jones Y, Fry E.E, Ren J, Stuart D. Hand-foot-and-mouth disease virus receptor KREMEN1 binds the canyon of Coxsackie Virus A10. Nature Communications 11, 38 (2020).

2019年度

  15. Wang N#, Zhao D#, Wang J#, Zhang Y#, Wang M, Gao Y, Li F, Wang J, Bu Z*, Rao Z*, Wang X*, Architecture of African swine fever virus and implications for viral assembly, Science, 2019, 366(6465): 640-644

  16. Cao L#, Liu P#, Yang P, Gao Q, Li H, Sun Y, Zhu L, Lin J, Dan S*, Rao Z*, Wang X*, Structural basis for neutralization of hepatitis A virus informs a rational design of highly potent inhibitors, PLoS Biology, 2019,17(4): e3000229

  17. Colibus L.D, Roine E, Walter T.S, Ilca S.L, Wang X, Wang N, Roseman A.M, Bamford D., Huiskonen J.T, Stuart D.I. Assembly of complex viruses exemplified by a halophilic euryarchaeal virus, Nature Communications 10, 1456 (2019).

  18. Zhou D, Zhao Y, Kotecha A, Fry E.E, Kelly J.T, Wang X, Rao Z, Rowlands D.J, Ren J, Stuart D.I. Unexpected mode of engagement between enterovirus 71 and its receptor SCARB2. Nature Microbiology 4, 414-419 (2019).

  19. Lu X, Xiao H, Li S, Pang X, Song J, Liu S, Cheng H, Li Y, Wang X, Huang C, Guo T, Ter Meulen J, Daffis S, Yan J, Dai L, Rao Z, Klenk HD, Qi J, Shi Y, Gao GF. Double Lock of a Human Neutralizing and Protective Monoclonal Antibody Targeting the Yellow Fever Virus Envelope. Cell Reports. 2019 Jan 8;26(2):438-446.e5.

2018年度

  20. Yuan S#, Wang J#, Zhu D#, Wang N, Gao Q, Chen W, Wang J*, Zhang X*, Liu H*, Rao Z*, Wang X*, Cryo-EM structure of a Herpesvirus capsid at 3.1A, Science, 2018, 360 (6384): 48-58

  21. Zhu L#*, Sun Y#, Fan J#, Zhu B, Cao L, Gao Q, Zhang Y*, Liu H, Rao Z*, Wang X*, Structures of Coxsackievirus A10 unveil the molecular mechanisms of receptor binding and viral uncoating, Nature Communications, 2018, 9: 4985

  22. Wang J#, Yuan S#, Zhu D#, Tang H, Wang N, Chen W, Gao Q, Li Y, Wang J, Liu H*, Zhang X*, Rao Z*, Wang X*, Structure of the herpes simplex virus type 2 C-capsid with capsid-vertex-specific component, Nature Communications, 2018, 9: 3668

  23. Qiu X#, Lei Y#, Yang P, Gao Q, Wang N, Cao L, Yuan S, Huang X, Deng Y, Ma W, Ding T, Zhang F, Wu X, Hu J, Liu S, Qin C, Wang X*, Xu Z*, Rao Z*, Structural basis for neutralization of Japanese encephalitis virus by two potent therapeutic antibodies, Nature Microbiology, 2018, 3: 287-294

  24. Huo Y#*, Li T, Wang N, Dong Q, Wang X*, Jiang T*, Cryo-EM structure of Type III-A CRISPR effector complex, Cell Research, 2018, 28: 1195-1197

  25. Zhu L#, Xu K#, Wang N#, Cao L, Wu J, Gao Q, Fry E.E, Stuart D.I, Rao Z, Wang J, Wang X*, Neutralization Mechanisms of Two Highly Potent Antibodies against Human Enterovirus 71, mBio, 2018, 9: e01013-18

  26. Zhu D, Wang X, Fang Q, Van Etten J, Rossmann M.G, Rao Z, Zhang X, Pushing the resolution limit by correcting the Ewald sphere effect in single-particle Cryo-EM reconstructions. Nature Communications 9, 1552 (2018).

  27. Xie DY, Liu ZY, Nian QG, Zhu L, Wang N, Deng YQ, Zhao H, Ji X, Li XF, Wang X, Shi PY, Qin CF. A single residue in the αB helix of the E protein is critical for Zika virus thermostability. Emerging Microbes & Infections. 2018 Jan 24;7(1):5

2017年度及以前

  28. Wang X#*, Zhu L#, Dang M#, Hu Z#, Gao Q, Yuan S, Sun Y, Zhang B, Ren J, Kotecha A, Walter T.S, Wang J*, Fry E.E*, Stuart D.I*, Rao Z*, Potent neutralization of hepatitis A virus reveals a receptor mimic mechanism and the receptor recognition site, Proc.Natl.Acad.Sci.USA, 2017, 114: 770~775

  29. Wang X#*, Li S#, Zhu L#, Nian Q#, Yuan S, Gao Q, Hu Z, Ye Q, Li X, Xie D, Shaw N, Wang J, Walter T.S, Huiskonen J.T, Fry E.E, Qin C*, Stuart D.I*, Rao Z*, Near-atomic structure of Japanese encephalitis virus reveals critical determinants of virulence and stability, Nature Communications, 2017, 8: 14

  30. Yuan L, Huang X, Liu Z, Zhang F, Zhu X, Yu J, Ji X, Xu Y, Li G, Li C, Wang H, Deng Y, Wu M, Cheng M, Ye Q, Xie D, Li X, Wang X, Shi W, Hu B, Shi P, Xu Z, Qin C. A single mutation in the prM protein of Zika virus contributes to fetal microcephaly. Science,17 2017: 933-936

  31. Zhang X#, Yang P#, Wang N, Zhang J, Li J, Guo H, Yin X, Rao Z, Wang X*, Zhang L*, The binding of a monoclonal antibody to the apical region of SCARB2 blocks EV71 infection, Protein & Cell, 2017, 8: 590-600

  32. Zhu L#, Wang X#, Ren J, Kotecha A, Walter T.S, Yuan S, Yamashita T, Tuthill T.J, Fry E.E, Rao Z*, Stuart D.I*, Structure of human Aichi virus and implications for receptor binding, Nature Microbiology, 2016, 1: 16150

  33. Wang X#, Ren J#, Gao Q#, Hu Z, Sun Y, Li X, Rowlands D.J, Yin W, Wang J*, Stuart D.I*, Rao Z*, Fry E.E, Hepatitis A virus and the origins of picornaviruses, Nature, 2015, 517: 85-88

  34. Zhu L#, Wang X#, Ren J, Porta C, Wenham H, Ekstrom J.O, Panjwani A, Knowles N.J, Kotecha A, Siebert A.C, Lindberg M, Fry E.E, Rao Z, Tuthill T.J, Stuart D.I*, Structure of Ljungan virus provides insight into genome packaging of this picornavirus, Nature Communications, 2015, 6: 8316

  35. Colibus L.D#, Wang X#, Tijsma A, Neyts J, Spyrou J.A, Ren J, Grimes j.M, Puerstinger G, Leyssen P, Fry E.E, Rao Z*, Stuart D.I*, Structure Elucidation of Coxsackievirus A16 in Complex with GPP3 Informs a Systematic Review of Highly Potent Capsid Binders to Enteroviruses, PLoS Pathog, 2015, 11: e1005165

  36. Ren J, Wang X, Zhu L, Hu Z, Gao Q, Yang P, Li X, Wang J, Shen X, Fry E.E, Rao Z*, Stuart D.I*, Structures of Coxsackievirus A16 Capsids with Native Antigenicity: Implications for Particle Expansion, Receptor Binding, and Immunogenicity, Journal of Virology, 2015, 89: 10500-10511

  37. Yuan S#, Cao L, Ling H, Dang M, Sun Y, Zhang X, Chen Y, Zhang L, Su D, Wang X*, Rao Z*, TIM-1 acts a dual-attachment receptor for Ebolavirus by interacting directly with viral GP and the PS on the viral envelope, Protein & Cell, 2015, 6: 814-824

  38. Colibus D.L#, Wang X#, Spyrou J.A, Kelly J, Ren J, Grimes J.M, Puerstinger G, Stonehouse N, Walter T.S, Hu Z, Wang J, Li X, Peng W, Rowlands D.J, Fry E.E., Rao Z*, Stuart D.I*, More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules, Nature Structural & Molecular Biology, 2014, 21: 282-288

  39. Dang M#, Wang X#, Wang Q, Wang Y, Lin J, Sun Y, Li X, Zhang L, Lou Z, Wang J, Rao Z*, Molecular mechanism of SCARB2-mediated attachment and uncoating of EV71, Protein & Cell, 2014, 5: 692-703

  40. Ren J#, Wang X#, Hu Z, Gao Q, Sun Y, Li X, Porta C, Walter T.S, Gilbert R.J, Zhao Y, Axford D, Williams M, McAuley K, Rowlands D.J, Yin W, Wang J*, Stuart D.I*, Rao Z, Fry.E.E, Picornavirus uncoating intermediate captured in atomic detail, Nature Communications, 2013, 4: 1929

  41. Wang L, Li J, Wang X, Liu W, Zhang XC, Li X, Rao Z. Structure analysis of the extracellular domain reveals disulfide bond forming-protein properties of Mycobacterium tuberculosis Rv2969c. Protein Cell. 2013 Aug;4(8):628-40.

  42. Sun Y#, Wang X#, Yuan S, Dang M, Li X, Zhang X, Rao Z*, An open conformation determined by a structural switch for 2A protease from coxsackievirus A16, Protein & Cell, 2013, 4: 782-792

  43. Wang X#, Peng W#, Ren J#, Hu Z, Xu J, Lou Z, Li X, Yin W, Shen X, Porta C, Walter T.S, Evans G, Axford D, Owen R, Rowlands D.J, Wang J*, Stuart D.I*, Fry E.E*, Rao Z*, A sensor-adaptor mechanism for enterovirus uncoating from structures of EV71, Nature Structural & Molecular Biology, 2012, 19: 424-429

  44. Xu J, Peng W, Sun Y, Wang X, Xu Y, Li X, Gao G, Rao Z. Structural study of MCPIP1 N-terminal conserved domain reveals a PIN-like RNase. Nucleic Acids Res. 2012 Aug;40(14):6957-65.

 

(资料来源:王祥喜研究员,2020-12-31)