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Filovirus

1.   Pathogenic Mechanisms of Flaviviruses

Flaviviruses are arthropod-borne viruses that include several severe pathogens prevalent in humans, such as Zika virus (ZIKV), dengue virus (DENV), West Nile virus (WNV), and yellow fever virus (YFV). We are dedicated to studying how these viruses enter host cells and cause disease, including the host receptors of flaviviruses, their replication mechanisms, and animal models of pathogenesis. Previously, we discovered that Zika virus infection not only causes microcephaly in newborns but also leads to testicular damage and infertility (Figure 1), revealing a novel mechanism on the potential pathogenesis of Zika virus on human health (Cell, 2017). We also elucidated the infection and immune characteristics of Zika virus in immune-privileged organs (J. Virol., 2024).

 

2.   Structural and Functional Biology of Flaviviruses

The structural and functional analysis of flaviviral proteins provides a critical foundation for understanding viral pathogenesis and designing vaccines and drugs. We focus on studying the structural features of key viral proteins involved in flavivirus entry, replication, and pathogenesis. In previous studies, we resolved the structures of several key proteins of Zika and other flaviviruses (Figure 2), including the envelope (E) protein (Cell Host Microbe, 2016; J. Virol., 2019), capsid (C) protein (J. Mol. Biol., 2018), nonstructural protein 1 (NS1) (Nat. Struct. Mol. Biol., 2016; EMBO J, 2016), nonstructural protein 3 (NS3) (EMBO J., 2017), and nonstructural protein 5 (NS5) (Trends Biochem. Sci, 2017). These structural insights have provided a important basis for understanding the Zika virus life cycle and pathogenic mechanisms, as well as identifying targets for vaccine and drug development.

 

3.   Vaccines and Monoclonal Antibodies for Flaviviruses

Vaccines and monoclonal antibodies are essential for preventing and controlling flavivirus infections. We are committed to designing and developing novel flavivirus vaccines and monoclonal antibodies for the prevention and treatment of flavivirus infections. Previously, we developed a Zika vaccine based on a chimpanzee adenovirus vector (J. Virol., 2018) and, through rational design, created a novel Zika vaccine that eliminates antibody-dependent enhancement (ADE) of dengue virus infection, revealing the immunological basis for this ADE elimination through immunedominance switch (Figure 3) (Nat. Immunol., 2021). We also isolated protective monoclonal antibodies targeting the E protein from Zika convalescent patients (Sci. Transl. Med., 2016) and discovered a monoclonal antibody, 1G5.3, that provides protection against multiple flaviviruses. We were the first to elucidate the mechanism of broad-spectrum protective antibodies targeting NS1 (Figure 3) (Science, 2021). Additionally, we obtained several protective monoclonal antibodies against yellow fever virus and revealed their structural bases (Cell Rep., 2019; Innovation, 2022), as well as the structural basis of a neutralizing protective antibodie against louping ill virus (LIV) (J. Virol., 2019).

Figures and legends

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

Figure 2: Structural and functional determination of flaviviral proteins

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.