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Open Access 01-12-2020 | Tick-Borne Encephalitis | Research

The envelope protein of tick-borne encephalitis virus influences neuron entry, pathogenicity, and vaccine protection

Authors: Richard Lindqvist, Ebba Rosendal, Elvira Weber, Naveed Asghar, Sarah Schreier, Annasara Lenman, Magnus Johansson, Gerhard Dobler, Malena Bestehorn, Andrea Kröger, Anna K. Överby

Published in: Journal of Neuroinflammation | Issue 1/2020

Abstract

Background

Tick-borne encephalitis virus (TBEV) is considered to be the medically most important arthropod-borne virus in Europe. The symptoms of an infection range from subclinical to mild flu-like disease to lethal encephalitis. The exact determinants of disease severity are not known; however, the virulence of the strain as well as the immune status of the host are thought to be important factors for the outcome of the infection. Here we investigated virulence determinants in TBEV infection.

Method

Mice were infected with different TBEV strains, and high virulent and low virulent TBEV strains were chosen. Sequence alignment identified differences that were cloned to generate chimera virus. The infection rate of the parental and chimeric virus were evaluated in primary mouse neurons, astrocytes, mouse embryonic fibroblasts, and in vivo. Neutralizing capacity of serum from individuals vaccinated with the FSME-IMMUN® and Encepur® or combined were evaluated.

Results

We identified a highly pathogenic and neurovirulent TBEV strain, 93/783. Using sequence analysis, we identified the envelope (E) protein of 93/783 as a potential virulence determinant and cloned it into the less pathogenic TBEV strain Torö. We found that the chimeric virus specifically infected primary neurons more efficiently compared to wild-type (WT) Torö and this correlated with enhanced pathogenicity and higher levels of viral RNA in vivo. The E protein is also the major target of neutralizing antibodies; thus, genetic variation in the E protein could influence the efficiency of the two available vaccines, FSME-IMMUN® and Encepur®. As TBEV vaccine breakthroughs have occurred in Europe, we chose to compare neutralizing capacity from individuals vaccinated with the two different vaccines or a combination of them. Our data suggest that the different vaccines do not perform equally well against the two Swedish strains.

Conclusions

Our findings show that two amino acid substitutions of the E protein found in 93/783, A83T, and A463S enhanced Torö infection of neurons as well as pathogenesis and viral replication in vivo; furthermore, we found that genetic divergence from the vaccine strain resulted in lower neutralizing antibody titers in vaccinated individuals.

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Title: The envelope protein of tick-borne encephalitis virus influences neuron entry, pathogenicity, and vaccine protection
Authors: Richard Lindqvist
Ebba Rosendal
Elvira Weber
Naveed Asghar
Sarah Schreier
Annasara Lenman
Magnus Johansson
Gerhard Dobler
Malena Bestehorn
Andrea Kröger
Anna K. Överby
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Tick-Borne Encephalitis
Published in: Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-020-01943-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The envelope protein of tick-borne encephalitis virus influences neuron entry, pathogenicity, and vaccine protection

Abstract

Background

Method

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Method

Results

Conclusions

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