Identification of the flavivirus conserved residues in the envelope protein hinge region for the rational design of a candidate West Nile live-attenuated vaccine

Bailey E. Maloney, Kassandra L. Carpio, Ashley N. Bilyeu, Danielle R.D. Saunders, So Lee Park, Adrienne E. Pohl, Natalia Costa Ball, Janae L. Raetz, Claire Y. Huang, Stephen Higgs, Alan D.T. Barrett, Gleyder Roman-Sosa, Joanie L. Kenney, Dana L. Vanlandingham, Yan Jang S. Huang

Research output: Contribution to journalArticlepeer-review

Abstract

The flavivirus envelope protein is a class II fusion protein that drives flavivirus-cell membrane fusion. The membrane fusion process is triggered by the conformational change of the E protein from dimer in the virion to trimer, which involves the rearrangement of three domains, EDI, EDII, and EDIII. The movement between EDI and EDII initiates the formation of the E protein trimer. The EDI-EDII hinge region utilizes four motifs to exert the hinge effect at the interdomain region and is crucial for the membrane fusion activity of the E protein. Using West Nile virus (WNV) NY99 strain derived from an infectious clone, we investigated the role of eight flavivirus-conserved hydrophobic residues in the EDI-EDII hinge region in the conformational change of E protein from dimer to trimer and viral entry. Single mutations of the E-A54, E-I130, E-I135, E-I196, and E-Y201 residues affected infectivity. Importantly, the E-A54I and E-Y201P mutations fully attenuated the mouse neuroinvasive phenotype of WNV. The results suggest that multiple flavivirus-conserved hydrophobic residues in the EDI-EDII hinge region play a critical role in the structure–function of the E protein and some contribute to the virulence phenotype of flaviviruses as demonstrated by the attenuation of the mouse neuroinvasive phenotype of WNV. Thus, as a proof of concept, residues in the EDI-EDII hinge region are proposed targets to engineer attenuating mutations for inclusion in the rational design of candidate live-attenuated flavivirus vaccines.

Original languageEnglish (US)
Article number172
Journalnpj Vaccines
Volume8
Issue number1
DOIs
StatePublished - Dec 2023

ASJC Scopus subject areas

  • Immunology
  • Pharmacology
  • Infectious Diseases
  • Pharmacology (medical)

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