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.
Highlights
Several different flaviviruses may cause encephalitis, Japanese encephalitis virus is the most significant, being responsible for thousands of deaths each year in Asia
Low resolution cryo-electron microscopy structures of mature and immature West Nile virus (WNV), recent near atomic resolution cryo-EM structures of DENV2, Zika virus (ZIKV) and ex situ crystal structures of some domains of E have been reported[17,18,19,20,21,22,23], there is no in situ structural information at high resolution available for encephalitic flaviviruses
The structure reveals unusual “holes” between two monomers within a dimer, formed by cooperative shifts of the k-l hairpin, and i-j, E0-F0 and B0-C0 loops. These holes are surrounded by five encephalitis-specific motifs, which have been proposed to play a key role in the attachment of the encephalitic flaviviruses to their receptor(s)
Summary
Several different flaviviruses may cause encephalitis, Japanese encephalitis virus is the most significant, being responsible for thousands of deaths each year in Asia. We identify structural elements modulating viral stability, notably Gln[264] of E, which, when replaced by His[264] 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. The structure reveals unusual “holes” between two monomers within a dimer, formed by cooperative shifts of the k-l hairpin, and i-j, E0-F0 and B0-C0 loops These holes are surrounded by five encephalitis-specific motifs, which have been proposed to play a key role in the attachment of the encephalitic flaviviruses to their receptor(s). The Q264H mutation observed in an attenuated strain of JEV increases virus stability, hindering the series of conformational changes in the virion required for infection Our studies on this attenuated strain of JEV further identify amino acids that impart neurovirulence in mice. The probable mechanism of attenuation of neurovirulence and its therapeutic implications are discussed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
