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The envelope protein of tick-borne encephalitis virus influences neuron entry, pathogenicity, and vaccine protection
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.ORCID iD: 0000-0001-8512-0535
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
School of Medical Sciences, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
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2020 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 17, no 1, article id 284Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2020. Vol. 17, no 1, article id 284
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
URN: urn:nbn:se:umu:diva-176174DOI: 10.1186/s12974-020-01943-wISI: 000576160400001PubMedID: 32988388Scopus ID: 2-s2.0-85092043389OAI: oai:DiVA.org:umu-176174DiVA, id: diva2:1482936
Funder
Swedish Research Council, 2011-2795Swedish Research Council, 2017-02438Available from: 2020-10-27 Created: 2020-10-27 Last updated: 2023-04-25Bibliographically approved
In thesis
1. Host-pathogen interactions during tick-borne flavivirus infection: pathogenesis, tropism and tools
Open this publication in new window or tab >>Host-pathogen interactions during tick-borne flavivirus infection: pathogenesis, tropism and tools
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Värd-patogen-interaktioner vid fästingburen flavivirus infektion : patogenes, tropism och verktyg
Abstract [en]

Tick-borne encephalitis virus (TBEV) is a neurotropic member of the genus Flavivirus. It may transmit to humans through the bite of an infected tick or consumption of unpasteurized dairyproducts, and causes tick-borne encephalitis (TBE). TBE constitutes a significant health burden in Eurasia, with more than 10,000 cases reported every year. In this thesis, I have investigated the role of the innate immune response in restricting infection in the central nervous system (CNS), identified virulence factors and developed a new model system to study the structural proteins of TBEV.

Viral tropism is important for understanding underlying mechanisms of pathology. In the first part,we combined whole-brain imaging with single nuclei RNA-sequencing after infection of wildtype (WT) and interferon (IFN) α/β receptor knockout (Ifnar-/-) mice by Langat virus (LGTV), a low-virulent model for TBEV. We found that absence of type I IFN signaling changes viral tropism and leads to an impaired inflammatory response. For neurons, astrocytes, and microglia we also compared the response to LGTV infection in vivo with the response of primary monocultures infected in vitro. Primary cells are often used for mechanistic studies of neurotropic viruses, but we found limited overlap in altered pathways between in vivo and in vitro, which emphasizes the role of cellular crosstalk in shaping the transcriptional response to infection in the brain.

The second part addresses viral determinants of pathogenicity. By comparing disease progression induced by different TBEV strains in a mouse model, we identified TBEV 93/783 as a highly virulentstrain belonging to the European subtype. We could show that two unusual amino acid substitutions in the envelope (E) protein of 93/783 enhanced neurovirulence and contributed to pathogenesis. To facilitate further studies of the structural proteins of TBEV, we generated and thoroughlycharacterized a chimeric virus with the pre-membrane (prM) and ecto-E protein of TBEV 93/783 in the genetic background of LGTV. The chimeric virus shows similar growth kinetics as the parental LGTV in vitro but is less pathogenic in our mouse model. Meanwhile, it remained neurovirulent and structurally similar to TBEV, making it a useful tool for studying the structural proteins of TBEV under lower biosafety conditions. Taken together, these findings deepen our understanding of what determines the outcome of tick-borne flavivirus infection and the utility of the available model systems for studying disease mechanisms. 

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2023. p. 61
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2244
Keywords
Tick-borne encephalitis virus, Langat virus, pathogenesis, type I interferons, central nervous system, neuroinflammation, structural proteins
National Category
Microbiology in the medical area Infectious Medicine
Research subject
Infectious Diseases; Microbiology
Identifiers
urn:nbn:se:umu:diva-207013 (URN)978-91-8070-072-6 (ISBN)978-91-8070-071-9 (ISBN)
Public defence
2023-05-26, Sal B, 9 tr., Tandläkarhögskolan, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2023-04-28 Created: 2023-04-25 Last updated: 2023-04-26Bibliographically approved

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Lindquist, RichardRosendal, EbbaWeber, ElviraLenman, AnnasaraÖverby, Anna K.

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