The Structure of Inactivated Mature Tick-borne Encephalitis Virus at 3.0 Å Resolution

Overview

Journal Emerg Microbes Infect

Specialty Infectious Diseases

Date 2024 Mar 11

PMID 38465849

Authors

Evgeny B Pichkur

Mikhail F Vorovitch

Alla L Ivanova

Elena V Protopopova

Valery B Loktev

Dmitry I Osolodkin

Aydar A Ishmukhametov

Valeriya R Samygina

Affiliations

Soon will be listed here.

Abstract

Tick-borne encephalitis virus (TBEV) causes a severe disease, tick-borne encephalitis (TBE), that has a substantial epidemiological importance for Northern Eurasia. Between 10,000 and 15,000 TBE cases are registered annually despite the availability of effective formaldehyde-inactivated full-virion vaccines due to insufficient vaccination coverage, as well as sporadic cases of vaccine breakthrough. The development of improved vaccines would benefit from the atomic resolution structure of the antigen. Here we report the refined single-particle cryo-electron microscopy (cryo-EM) structure of the inactivated mature TBEV vaccine strain Sofjin-Chumakov (Far-Eastern subtype) at a resolution of 3.0 Å. The increase of the resolution with respect to the previously published structures of TBEV strains Hypr and Kuutsalo-14 (European subtype) was reached due to improvement of the virus sample quality achieved by the optimized preparation methods. All the surface epitopes of TBEV were structurally conserved in the inactivated virions. ELISA studies with monoclonal antibodies supported the hypothesis of TBEV protein shell cross-linking upon inactivation with formaldehyde.

Citing Articles

MPicker: visualizing and picking membrane proteins for cryo-electron tomography.

Yan X, Li S, Huang W, Wang H, Zhao T, Huang M Nat Commun. 2025; 16(1):472.

PMID: 39774981 PMC: 11707294. DOI: 10.1038/s41467-024-55767-w.

An Inactivated West Nile Virus Vaccine Candidate Based on the Lineage 2 Strain.

Vorovitch M, Tuchynskaya K, Kruglov Y, Peunkov N, Mostipanova G, Kholodilov I Vaccines (Basel). 2025; 12(12.

PMID: 39772058 PMC: 11680355. DOI: 10.3390/vaccines12121398.

Structural diversity of tick-borne encephalitis virus particles in the inactivated vaccine based on strain Sofjin.

Moiseenko A, Zhang Y, Vorovitch M, Ivanova A, Liu Z, Osolodkin D Emerg Microbes Infect. 2023; 13(1):2290833.

PMID: 38073510 PMC: 10930090. DOI: 10.1080/22221751.2023.2290833.

References

Barrows N, Campos R, Liao K, Prasanth K, Soto-Acosta R, Yeh S . Biochemistry and Molecular Biology of Flaviviruses. Chem Rev. 2018; 118(8):4448-4482. PMC: 5937540. DOI: 10.1021/acs.chemrev.7b00719. View

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

Punjani A, Rubinstein J, Fleet D, Brubaker M . cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat Methods. 2017; 14(3):290-296. DOI: 10.1038/nmeth.4169. View

Deviatkin A, Karganova G, Vakulenko Y, Lukashev A . TBEV Subtyping in Terms of Genetic Distance. Viruses. 2020; 12(11). PMC: 7692686. DOI: 10.3390/v12111240. View

Rosenthal P, Henderson R . Optimal determination of particle orientation, absolute hand, and contrast loss in single-particle electron cryomicroscopy. J Mol Biol. 2003; 333(4):721-45. DOI: 10.1016/j.jmb.2003.07.013. View

Moiseenko A, Zhang Y, Vorovitch M, Ivanova A, Liu Z, Osolodkin D . Structural diversity of tick-borne encephalitis virus particles in the inactivated vaccine based on strain Sofjin. Emerg Microbes Infect. 2023; 13(1):2290833. PMC: 10930090. DOI: 10.1080/22221751.2023.2290833. View

Croll T . ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps. Acta Crystallogr D Struct Biol. 2018; 74(Pt 6):519-530. PMC: 6096486. DOI: 10.1107/S2059798318002425. View

Khare B, Klose T, Fang Q, Rossmann M, Kuhn R . Structure of Usutu virus SAAR-1776 displays fusion loop asymmetry. Proc Natl Acad Sci U S A. 2021; 118(34). PMC: 8403871. DOI: 10.1073/pnas.2107408118. View

Prasad V, Miller A, Klose T, Sirohi D, Buda G, Jiang W . Structure of the immature Zika virus at 9 Å resolution. Nat Struct Mol Biol. 2017; 24(2):184-186. PMC: 5296287. DOI: 10.1038/nsmb.3352. View

10.

Fuzik T, Formanova P, Ruzek D, Yoshii K, Niedrig M, Plevka P . Structure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody. Nat Commun. 2018; 9(1):436. PMC: 5789857. DOI: 10.1038/s41467-018-02882-0. View

11.

Kostyuchenko V, Lim E, Zhang S, Fibriansah G, Ng T, Ooi J . Structure of the thermally stable Zika virus. Nature. 2016; 533(7603):425-8. DOI: 10.1038/nature17994. View

12.

Jiang W, Tang L . Atomic cryo-EM structures of viruses. Curr Opin Struct Biol. 2017; 46:122-129. PMC: 5683926. DOI: 10.1016/j.sbi.2017.07.002. View

13.

de Oliveira G, Silva J . Cryo-EM to visualize the structural organization of viruses. Curr Opin Virol. 2021; 49:86-91. DOI: 10.1016/j.coviro.2021.04.011. View

14.

Berman H, Westbrook J, Feng Z, Gilliland G, Bhat T, Weissig H . The Protein Data Bank. Nucleic Acids Res. 1999; 28(1):235-42. PMC: 102472. DOI: 10.1093/nar/28.1.235. View

15.

Newton N, Hardy J, Modhiran N, Hugo L, Amarilla A, Bibby S . The structure of an infectious immature flavivirus redefines viral architecture and maturation. Sci Adv. 2021; 7(20). PMC: 8121421. DOI: 10.1126/sciadv.abe4507. View

16.

Ruzek D, Avsic Zupanc T, Borde J, Chrdle A, Eyer L, Karganova G . Tick-borne encephalitis in Europe and Russia: Review of pathogenesis, clinical features, therapy, and vaccines. Antiviral Res. 2019; 164:23-51. DOI: 10.1016/j.antiviral.2019.01.014. View

17.

Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O . Highly accurate protein structure prediction with AlphaFold. Nature. 2021; 596(7873):583-589. PMC: 8371605. DOI: 10.1038/s41586-021-03819-2. View

18.

Postler T, Beer M, Blitvich B, Bukh J, de Lamballerie X, Drexler J . Renaming of the genus Flavivirus to Orthoflavivirus and extension of binomial species names within the family Flaviviridae. Arch Virol. 2023; 168(9):224. DOI: 10.1007/s00705-023-05835-1. View

19.

Stiasny K, Holzmann H, Heinz F . Characteristics of antibody responses in tick-borne encephalitis vaccination breakthroughs. Vaccine. 2009; 27(50):7021-6. DOI: 10.1016/j.vaccine.2009.09.069. View

20.

Agirre J, Atanasova M, Bagdonas H, Ballard C, Basle A, Beilsten-Edmands J . The CCP4 suite: integrative software for macromolecular crystallography. Acta Crystallogr D Struct Biol. 2023; 79(Pt 6):449-461. PMC: 10233625. DOI: 10.1107/S2059798323003595. View