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黄病毒

1. 黄病毒的致病机制

黄病毒属虫媒传播病毒，包括多种在人群中流行的严重病原体，例如寨卡病毒（ZIKV）、登革病毒（DENV）、西尼罗病毒（WNV）和黄热病毒（YFV）等。我们致力于研究这些病毒如何进入宿主细胞并引起宿主致病的机制，包括黄病毒的宿主受体、繁殖机制以及感染致病的动物模型等。前期我们发现寨卡病毒感染除了能引起新生儿小头症之外，也能引起睾丸损伤并导致不育（图1），从全新的角度揭示了寨卡病毒对人类健康可能存在的影响（Cell，2017）;也揭示了寨卡病毒在免疫豁免器官中的感染与免疫特性（J.Virol., 2024）。

 

2. 黄病毒的结构与功能

黄病毒蛋白的结构与功能分析为理解病毒的致病机制以及疫苗与药物设计提供重要的基础。我们致力于研究参与黄病毒入侵、复制和致病过程中的关键病毒蛋白的结构特征。前期的研究我们解析了一些列寨卡等黄病毒关键蛋白的结构（图2），包括囊膜（E）蛋白（Cell Host Microbe, 2016； J.Virol.,2019）、核衣壳（C）蛋白(J.Mol.Biol.,2018)、非结构蛋白1(NS1) (Nat. Struct. Mol. Biol., 2016; EMBO J, 2016)，非结构蛋白3(NS3) (EMBO J., 2017)，和非结构蛋白5（NS5）(Trends Biochem. Sci, 2017). 这些结构的解析为理解寨卡病毒生命周期和致病机制提供了重要基础，也为疫苗和药物的设计提供了靶点。

 

3. 黄病毒的疫苗与单克隆抗体

疫苗与单克隆抗体是防控黄病毒感染。我们致力于设计和开发新型黄病毒疫苗与单克隆抗体用于预防和治疗黄病毒的感染。前期我们开发了基于黑猩猩腺病毒载体的寨卡疫苗 (J. Virol.,2018)，并通过理性设计获得了消除登革抗体依赖增强（ADE）的新型寨卡疫苗，并揭示了其通过免疫优势转换消除登革ADE的免疫学基础（图3） (Nat. Immunol.,2021)；我们从寨卡康复病人体内筛选出靶向E蛋白的保护性单克隆抗体（Sci.Transl.Med.,2016）, 发现了一株对多种黄病毒都有保护效果的单克隆抗体1G5.3，并首次揭示了NS1广谱保护性抗体的作用机制（图3） (Science,2021),此外，我们还获得了多种黄热病毒保护性单克隆抗体及并揭示其结构基础（Cell Rep.,2019; Innovation,2022），揭示了羊跳跃病毒（LIV）中和保护性抗体的结构基础（J Virol.,2019）。

Figures and legends

图1：寨卡病毒感染引起睾丸萎缩和雄性不育（Cell，2017）

Figure1：Zika virus infection causes testis damage and male infertility.

图2：黄病毒的病毒结构与功能解析

Figure 2: Structural and functional determination of flaviviral proteins

图3：黄病毒的疫苗与单克隆抗体设计与开发

Figure 3: Design and development of vaccines and monoclonal antibodies against flaviviruses


Publications

1.      Modhiran, N., Song, H., Liu, L., Bletchly, C., Brillault, L., Amarilla, A. A., Xu, X., Qi, J., Chai, Y., Cheung, S. T. M., Traves, R., Setoh, Y. X., Bibby, S., Scott, C. A. P., Freney, M. E., Newton, N. D., Khromykh, A. A., Chappell, K. J., Muller, D. A., Stacey, K. J., Landsberg, M. J., Shi, Y, Gao*, G. F., Young*, P. R. and Watterson*, D., 2021, A broadly protective antibody that targets the flavivirus NS1 protein. Science, 371 (6525): 190-194.

2.      Ma, W., Li, S., Ma, S., Jia, L., Zhang, F., Zhang, Y., Zhang, J., Wong, G., Zhang, S., Lu, X., Liu, M., Yan, J., Li, W., Qin, C., Han, D., Qin, C., Wang, N., Li*, X. and Gao*, G. F., 2016, Zika virus causes testis damage and leads to male infertility in mice, Cell, 168 (3): 542.

3.      Gao*, G. F., 2018, From “A”IV to “Z”IKV: attacks from emerging and re-emerging pathogens (Commentary). Cell, 172 (6): 1157-1159.

4.      Dai*, L., Xu, K., Li, J., Huang, Q., Song, J., Han, Y., Zheng, T., Gao, P., Lu, X., Yang, H., Liu, K., Xia, Q., Wang, Q., Chai, Y., Qi, J., Yan*, J. and Gao*, G. F., 2021, Protective Zika vaccines engineered to eliminate enhancement of dengue infection via immunodominance switch. Nature Immunology, 22 (8): 958-968.

5.      Dai, L., Song, J., Lu, X., Deng, Y. Q., Mosyoki, A. M., Cheng, H., Zhang, Y., Yuan, Y., Song, H., Haywood, J., Xiao, H., Yan, J., Shi, Y., Qin*, C. F., Qi*, J. and Gao*, G. F., 2016, Structures of the Zika virus envelope protein and its complex with a flavivirus broadly protective antibody. Cell Host and Microbe, 19 (5): 696-704.

6.      Wang, Q., Yang, H., Liu, X., Dai, L., Ma, T., Qi, J., Wong, G., Peng, R., Liu, S., Li, J., Li, S., Song, J., Liu, J., He, J., Yuan, H., Xiong, Y., Liao, Y., Li, J., Yang, J., Tong, Z., Griffin, B. D., Bi, Y., Liang, M., Xu, X., Qin, C., Cheng, G., Zhang, X., Wang, P., Qiu, X., Kobinger, G., Shi, Y., Yan*, J. and Gao*, G. F., 2016, Molecular determinants of human neutralizing antibodies isolated from a patient infected with Zika virus. Science Translational Medicine, 8 (369): 369ra179. (Cover story)

7.      Song, H., Qi, J., Haywood, J., Shi*, Y. and Gao*, G. F., 2016, Zika virus NS1 structure reveals diversity of electrostatic surfaces among flaviviruses. Nature Structural and Molecular Biology, 23 (5): 456-458.

8.      Xu, X., Song, H., Qi, J., Liu, Y., Wang, H., Su, C., Shi*, Y. and Gao*, G. F., 2016, Contribution of intertwined loop to membrane association revealed by Zika virus full-length NS1 structure. The EMBO Journal, 35 (20): 2170-2178. (Cover story)

9.       

10.   Wong, G. and Gao*, G. F., 2018, Did Zika virus evolve to be more dangerous? A new clue towards neurovirulence (Research Highlight). National Science Review, 5 (2): 120-121.

11.   Xu, K., Song, Y., Dai, L., Zhang, Y., Lu, X., Xie, Y., Zhang, H., Cheng, T., Wang, Q., Huang, Q., Bi, Y., Liu, W. J., Liu, W., Li, X., Qin, C., Shi, Y., Yan, J., Zhou*, D. and Gao*, G. F., 2018, Recombinant AdC7-M/E protects against Zika virus infection and testis damage. Journal of Virology, 92 (6): e01722-17.

12.   Molecular basis of a protective/neutralizing monoclonal antibody targeting envelope proteins of both tick-borne encephalitis virus and louping ill virus. Journal of Virology, 93 (8): e02132-18.

13.   Shang, Z., Song, H., Shi, Y., Qi*, J. and Gao*, G. F., 2018, Crystal structure of the capsid protein from Zika virus. Journal of Molecular Biology, 430 (7): 948-962.

14.   Li, Y., Chen, Z., Wu, L., Dai, L., Qi, J., Chai, Y., Li, S., Wang, Q., Tong, Z., Ma, S., Duan, X., Ren, S., Song, R., Liang, M., Liu, W., Yan*, J. and Gao*, G. F., 2022, A neutralizing-protective supersite of human monoclonal antibodies for yellow fever virus. The Innovation (Camb), 3 (6): 100323.

15.   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, H., Qi, J., Shi, Y. and Gao*, G. F., 2019, Double lock of a human neutralizing and protective monoclonal antibody targeting the yellow fever virus envelope. Cell Reports, 26 (2): 438-446.e5.

16.   Wang, H., Han, M., Qi, J., Hilgenfeld, R., Luo, T., Shi, Y., Gao*, G. F. and Song*, H., 2017, Crystal structure of the C-terminal fragment of NS1 protein from yellow fever virus. Science China Life Sciences, 60 (12): 1403-1406.

17.   Qi*, X., Wang, Y., Li, Y., Meng, Y., Chen, Q., Ma, J. and Gao*, G. F., 2015, The effects of socioeconomic and environmental factors on the incidence of Dengue fever in the Pearl River Delta, China, 2013, PLOS Neglected Tropical Diseases, 9 (10): e0004159.

18.   Shi, Y., Li, S., Wu, Q., Sun, L., Zhang, J., Pan, N., Wang, Q., Bi, Y., An, J., Lu, X., Gao*, G. F. and Wang*, X., 2018, Vertical transmission of the Zika virus causes neurological disorders in mouse offspring. Scientific Reports, 8 (1): 3541.

19.   Li*, X., Ma, W., Wong, G., Ma, S., Li, S., Bi, Y. and Gao*, G. F., 2018, A new threat to human reproduction system posted by Zika virus (ZIKV): from clinical investigations to experimental studies. Virus Research, 254: 10-14.

20.   Dai*, L., Wang, Q., Song, H. and Gao*, G. F., 2018, Zika virus envelope protein and antibody complexes. Sub-cellular Biochemistry, 88: 147-168.

21.   Zhang, Y., Zhang, H., Ma, W., Liu, K., Zhao, M., Zhao, Y., Lu, X., Zhang, F., Li*, X., Gao*, G. F. and Liu*, W. J., 2018, Evaluation of Zika virus-specific T-cell response in immuneprivileged organs on infected Ifnar1-/- mice. Journal of Visualized Experiments, 140: 58110.

22.   Duan, W., Song, H., Wang, H., Chai, Y., Su, C., Qi, J., Shi*, Y. and Gao*, G. F., 2017, The crystal structure of Zika virus NS5 reveals conserved drug targets. The EMBO Journal, 36 (7): 919-933.

23.   Shi*, Y. and Gao*, G. F., 2017, Structural biology of the Zika virus. (Invited review) Trends in Biochemical Sciences, 42 (6): 443-456.

24.   Wong*, G. and Gao, G. F., 2017, An mRNA-based vaccine strategy against Zika. (Invited Research Highlight). Cell Research, 27 (9): 1077-1078.

25.   Wang*, Q., Yan, J. and Gao, G. F., 2017, Monoclonal antibodies against Zika virus: therapeutics and their implications for vaccine design. Journal of Virology, 91 (20): e01049-17.

26.   Huang, H., Li, S., Zhang, Y., Han, X., Jia, B., Liu, H., Liu, D., Tan, S., Wang, Q., Bi, Y., Liu, W. J., Hou, B., Gao*, G. F. and Zhang*, F., 2017, CD8+ T cell immune response in immunocompetent mice during Zika virus infection. Journal of Virology, 91 (22): e00900-17.

27.   Duan, X., Li, S., Wong, G., Wang, D., Wang, H., Lu, J., Bi, Y., Lu, X., Shi, Y., Yan, J., Fang*, M. and Gao*, G. F., 2017, Natural killer cells are activated and play a protective role against Zika virus infection in mice. Science Bulletin, 62 (14): 982-984.

28.   Shi*, W., Zhang, Z., Ling, C., Carr, M. J., Tong, Y. and Gao, G. F., 2016, Increasing genetic diversity of Zika virus in the Latin American outbreak. Emerging Microbes and Infections, 5 (7): e68.

29.   Zhang H, Xiao W, Zhao M, Zhang Y, Lu D, Lu S, Zhang Q, Peng W, Shu L, Zhang J, Liu S, Zong K, Wang P, Ye B, Zhang D, Li S, Tan S, Liu P, Zhao Y, Zhang F, Wang H, Lu X, Gao G.F, Liu J. Characterization of CD8+ T cells in immune-privileged organs of ZIKV-infected Ifnar1-/- mice. J Virol. 2024 Jan 23;98(1):e0078923.

30.   Zhang, H., Xiao, W., Zhao, M., Zhao, Y., Zhang, Y., Lu, D., Lu, S., Zhang, Q., Peng, W., Shu, L., Zhang, J., Liu, S., Zong, K., Wang, P., Ye, B., Li, S., Tan, S., Zhang, F., Zhou, J., Liu, P., Wu, G., Lu*, X., Gao*, G. F. and Liu*, W. J., 2022, The CD8+ and CD4+ T Cell immunogen Atlas of Zika virus reveals E, NS1 and NS4 proteins as the vaccine targets. Viruses, 14 (11): 2332.

31.   Wang, H., Li, X., Liu, L., Xu, Y., Ye, Q., Deng, Y.-Q., Huang, X., Zhao, H., Qin, E, Shi, P., Gao, G. F. and Qin*, C., 2016, The emerging duck flavivirus is not pathogenic for primates and is highly sensitive to mammalian interferon antiviral signaling. Journal of Virology, 90 (14): 6538-6548.

32.   Dai*, L., Wang, Q., Qi, J., Shi, Y., Yan J. and Gao*, G. F., 2016, Molecular basis of antibody-mediated neutralization and protection against flavivirus (Invited review). IUBMB Life, 68 (10): 783-791. (Cover story).

33.   Liu, P., Lu, H., Li S., Wu, Y., Gao*, G. F. and Su*, J., 2013, Duck egg drop syndrome virus: an emerging Tembusu-related flavivirus in China. Science China Life Sciences, 56: 701-710.

34.   Liu, P., Lu, H., Li, S., Moureau, G., Deng, Y. Q., Wang, Y., Zhang, L., Jiang, T., de Lamballerie, X., Qin, C., Gould, E. A., Su*, J. and Gao*, G. F., 2012, Genomic and antigenic characterization of the newly-emerging Chinese duck egg-drop syndrome flavivirus: genomic comparison with Tembusu and Sitiawan viruses. The Journal of General Virology, 93 (10): 2158-2170. 

35.   Su*, J., Li, S., Hu, X., Yu, X., Wang, Y., Liu, P., Lu, X., Zhang, G., Hu, X., Liu, D., Li, X., Su, W., Lu, H., Mok, N. S., Wang, P., Wang, M., Tian*, K. and Gao*, G. F., 2011, Duck egg-drop syndrome caused by BYD virus, a new Tembusu-related flavivirus. PLOS ONE, 6 (3): e18106.

36.   Gao, G. F., Hussain, M. H., Reid, H. W. and Gould, E. A., 1993, Classification of a new member of the TBE flavivirus subgroup by its immunological, pathogenetic and molecular characteristics: identification of subgroup-specific pentapeptides. Virus Research, 30 (2): 129-144.

37.   Gao, G. F., Zanotto, P. M. A., Holmes, E. C., Reid, H. W. and Gould, E. A., 1997, Molecular variation, evolution and geographical distribution of louping ill virus. Acta Virologica, 41 (2): 259-268.

38.   Gao, G. F., Hussain, M. H., Reid, H. W. and Gould, E. A., 1994, Identification of naturally occurring monoclonal antibody escape variants of louping ill virus. The Journal of General Virology, 75 (Pt 3): 609-614.

39.   Gao, G. F., Jiang, W. R., Hussain, M. H., Venugopal, K., Gritsun, T. S., Reid, H. W. and Gould, E. A., 1993, Sequencing and antigenic studies of a Norwegian virus isolated from encephalomyelitic sheep confirm the existence of louping ill virus outside Great Britain and Ireland. The Journal of General Virology, 74 (Pt 1): 109-114.

40.   Liu, J., Liu, B., Cao, Z., Inoue, S., Morita, K., Tian, K., Zhu, Q. and Gao*, G. F., 2008, Characterization and application of monoclonal antibodies specific to West Nile virus envelope protein. Journal of Virological Methods, 154 (2008): 20-26.

41.   Yuan, F., Lou, Z., Li, X., Chen, Y., Bell, J. I., Rao, Z. and Gao*, G. F., 2005, Refolding, crystallization and preliminary X-ray structural studies of the West Nile virus envelope (E) protein domain Ⅲ. Acta Crystallographica Section F Structural Biology and Crystallization Communications, 61 (Pt 4): 421-423.

 

Book Chapters:

1.    Edited by Hilgenfeld, R. and Vasudevan, S. G., Springer, Subcellular Biochemistry, 2018, Zika virus envelope protein and antibody complexes, Dai, L., Wang, Q., Song, H. and Gao, G. F.