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Associate Professor Lok is one of the recipients for the prestigious National Research Foundation fellowship. Dengue Virus (DENV) infects approximately 100 million people each year. Increased travel, together with global climate change will result in further geographical expansion of the territory of the dengue mosquito vector, Aedes aegypti. There is an urgent need to develop safe and effective dengue therapeutics and vaccine.
In vitro experiments have shown that non-neutralizing antibodies can enhance DENV infection of Fc receptor bearing macrophages, one of the natural host cells for the virus. This suggested that the presence of non-neutralizing epitopes in a vaccine could potentially increase the chances that a person who had received the vaccine would develop the severe form of the disease, dengue hemorrhagic fever. For this reason, a more promising approach for engineering an effective DENV vaccine is to focus on including neutralizing epitopes. Thus, mapping of neutralizing epitopes is a necessary component of DENV vaccine research. Furthermore, understanding the neutralization mechanism of antibodies and the entry of DENV into the host cells also could aid in the design of targeted therapeutics.
The research in her laboratory therefore, focuses on the understanding of the pathology of dengue virus infection and the mechanism of neutralization by antibodies and other molecules so as to facilitate the development of suitable vaccines and therapeutics. A combination of molecular, immunological, biochemical and structural techniques (x ray crystallography and cryoEM image reconstruction techniques) will be used to achieve these aims.
Shuijun Zhang, Victor A. Kostyuchenko, Thiam-Seng Ng, Xin-Ni Lim, Justin S.G. Ooi, Sebastian Lambert, Ter Yong Tan, Douglas G. Widman, Jian Shi, Ralph S. Baric and Shee-Mei Lok. (2016). Neutralization mechanism of a highly potent antibody against Zika virus. Nature Communications. Vol 7: 13679.
Kostyuchenko VA, Lim EX, Zhang S, Fibriansah G, Ng TS, Ooi JS, Shi J, Lok SM. (2016). Structure of the thermally stable Zika virus. Nature. 533:425-428.
Guntur Fibriansah, Kristie D. Ibarra, Thiam-Seng Ng, Scott A. Smith, Joanne L. Tan, Xin-Ni Lim, Justin S. G. Ooi, Victor A. Kostyuchenko, Jiaqi Wang, Aravinda M. de Silva, Eva Harris, James E. Crowe, Jr. and Shee-Mei Lok. (2015). A human antibody locks dengue virus E protein dimers and prevents antibody-enhanced severe disease. Science. Vol 349:88-91.
Guntur Fibriansah, Joanne L. Tan, Scott A. Smith, Ruklanthi de Alwis, Thiam-Seng Ng, Victor A. Kostyuchenko, Ramesh S. Jadi, Petra Kukkaro, Aravinda M. de Silva, James E. Crowe, Jr. and Shee-Mei Lok. (2015). A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins. Nature Communications. Vol 6:6341.
Shee-Mei Lok. (2015). The interplay of dengue virus morphological diversity and human antibodies. Trends in Microbiology. Vol 24(4):284-93.
Shee-Mei Lok. (2014). Human antibodies stop dengue virus by jamming its mechanics. Proceedings of National Academy of Sciences USA. Vol 111:1670-1671.
Victor A. Kostyuchenko, Pau Ling Chew, Thiam-Seng Ng, Shee-Mei Lok (2014). Near-atomic resolution cryo-EM structure of Dengue serotype 4 virus. Journal of Virology. Vol 88: 477-482.
Guntur Fibriansah, Joanne L. Tan, Ruklanthi de Alwis, Scott A. Smith, Thiam-Seng Ng, Victor A. Kostyuchenko, Kristie D. Ibarra, Eva Harris, Aravinda de Silva, James E. Crowe, Jr. and Shee-Mei Lok (2014). A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface. EMBO Molecular Medicine. Vol 6: 358-371.
Guntur Fibriansah, Thiam-Seng Ng, Victor A. Kostyuchenko, Jaime Lee, Sumarlin Lee, Jiaqi Wang, Shee-Mei Lok (2013). Structural Changes in Dengue Virus When Exposed to a Temperature of 37oC. Journal of Virology, Vol 87:7585-92.
Victor A Kostyuchenko, Qian Zhang, Joanne L Tan, Thiam-Seng Ng, Shee-Mei Lok (2013). Immature and mature Dengue serotype 1 virus structures provide insight into the maturation process. Journal of Virology. Vol 87:7700-7.
Ee Ping Teoh, Petra Kukkaro, En Wei Teo, Angeline Lim, Tze Tong Tan, Andy Yip, Wouter Schul, Myint Aung, Victor A. Kostyuchenko, Yee Sin Leo, Soh Ha Chan, Kenneth G.C. Smith, Eng Eong Ooi, D. Michael Kemeny, Grace K. Tan, Jowin K. W. Ng, Mah Lee Ng, Sylvie Alonso, Pei Yong Shi, Dale Fisher, Brendon Hanson, Shee-Mei Lok* and Paul A. MacAry*. (2012). The Structural Basis for Serotype-Specific Neutralization of Dengue Virus by a Natural Human Antibody. Science Translational Medicine. Vol 4:139 * co-corresponding authors
Li L, Lok SM, Yu IM, Zhang Y, Kuhn RJ, Chen J, Rossmann MG. (2008). Structure of the flavivirus precursor membrane-envelope protein complex and its implication for maturation. Science. 319: 1830-1834.
Lok SM, Kostyuchenko V, Nybakken GE, Holdaway HA, Battisti AJ, Sukupolvi-Petty S, Sedlak D, Fremont DH, Chipman PR, Roehrig JT, Diamond MS, Kuhn RJ, Rossmann MG. (2008). Binding of a neutralizing antibody to dengue virus resulted in an altered arrangement of the surface glycoproteins. Nature Structural and Molecular Biology. 15 (3): 312-317.
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