Near-atomic structure of Japanese encephalitis virus reveals critical determinants of virulence and stability

Xiangxi Wang (), Shi-Hua Li, Ling Zhu, Qing-Gong Nian, Shuai Yuan, Qiang Gao, Zhongyu Hu, Qing Ye, Xiao-Feng Li, Dong-Yang Xie, Neil Shaw, Junzhi Wang, Thomas S. Walter, Juha T. Huiskonen, Elizabeth E. Fry, Cheng-Feng Qin (), David I. Stuart () and Zihe Rao ()
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Xiangxi Wang: Chinese Academy of Science
Shi-Hua Li: Beijing Institute of Microbiology and Epidemiology
Ling Zhu: University of Oxford
Qing-Gong Nian: Beijing Institute of Microbiology and Epidemiology
Shuai Yuan: Chinese Academy of Science
Qiang Gao: Chinese Academy of Science
Zhongyu Hu: National Institutes for Food and Drug Control
Qing Ye: Beijing Institute of Microbiology and Epidemiology
Xiao-Feng Li: Beijing Institute of Microbiology and Epidemiology
Dong-Yang Xie: Beijing Institute of Microbiology and Epidemiology
Neil Shaw: Chinese Academy of Science
Junzhi Wang: National Institutes for Food and Drug Control
Thomas S. Walter: University of Oxford
Juha T. Huiskonen: University of Oxford
Elizabeth E. Fry: University of Oxford
Cheng-Feng Qin: Beijing Institute of Microbiology and Epidemiology
David I. Stuart: University of Oxford
Zihe Rao: Chinese Academy of Science

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract Although several different flaviviruses may cause encephalitis, Japanese encephalitis virus is the most significant, being responsible for thousands of deaths each year in Asia. The structural and molecular basis of this encephalitis is not fully understood. Here, we report the cryo-electron microscopy structure of mature Japanese encephalitis virus at near-atomic resolution, which reveals an unusual “hole” on the surface, surrounded by five encephalitic-specific motifs implicated in receptor binding. Glu138 of E, which is highly conserved in encephalitic flaviviruses, maps onto one of these motifs and is essential for binding to neuroblastoma cells, with the E138K mutation abrogating the neurovirulence and neuroinvasiveness of Japanese encephalitis virus in mice. We also identify structural elements modulating viral stability, notably Gln264 of E, which, when replaced by His264 strengthens a hydrogen-bonding network, leading to a more stable virus. These studies unveil determinants of neurovirulence and stability in Japanese encephalitis virus, opening up new avenues for therapeutic interventions against neurotropic flaviviruses.

Date: 2017
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DOI: 10.1038/s41467-017-00024-6

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