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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>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\u00ae and Encepur\u00ae or combined were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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 Tor\u00f6. We found that the chimeric virus specifically infected primary neurons more efficiently compared to wild-type (WT) Tor\u00f6 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\u00ae and Encepur\u00ae. 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings show that two amino acid substitutions of the E protein found in 93\/783, A83T, and A463S enhanced Tor\u00f6 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-020-01943-w","type":"journal-article","created":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T12:03:29Z","timestamp":1601294609000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The envelope protein of tick-borne encephalitis virus influences neuron entry, pathogenicity, and vaccine protection"],"prefix":"10.1186","volume":"17","author":[{"given":"Richard","family":"Lindqvist","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebba","family":"Rosendal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naveed","family":"Asghar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Schreier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annasara","family":"Lenman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Johansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Dobler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malena","family":"Bestehorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Kr\u00f6ger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6553-0940","authenticated-orcid":false,"given":"Anna K.","family":"\u00d6verby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,28]]},"reference":[{"key":"1943_CR1","doi-asserted-by":"publisher","first-page":"1861","DOI":"10.1016\/S0140-6736(08)60800-4","volume":"371","author":"L Lindquist","year":"2008","unstructured":"Lindquist L, Vapalahti O. Tick-borne encephalitis. Lancet. 2008;371:1861\u201371.","journal-title":"Lancet"},{"key":"1943_CR2","doi-asserted-by":"crossref","unstructured":"Beaute J, Spiteri G, Warns-Petit E, Zeller H. Tick-borne encephalitis in Europe, 2012 to 2016. Euro Surveill. 2018;23.","DOI":"10.2807\/1560-7917.ES.2018.23.45.1800201"},{"key":"1943_CR3","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1007\/s15010-016-0917-8","volume":"44","author":"L Markovinovic","year":"2016","unstructured":"Markovinovic L, Kosanovic Licina ML, Tesic V, Vojvodic D, Vladusic Lucic I, Kniewald T, Vukas T, Kutlesa M, Krajinovic LC. An outbreak of tick-borne encephalitis associated with raw goat milk and cheese consumption, Croatia, 2015. Infection. 2016;44:661\u20135.","journal-title":"Infection"},{"key":"1943_CR4","doi-asserted-by":"publisher","first-page":"806","DOI":"10.3201\/eid1905.121442","volume":"19","author":"N Hudopisk","year":"2013","unstructured":"Hudopisk N, Korva M, Janet E, Simetinger M, Grgic-Vitek M, Gubensek J, Natek V, Kraigher A, Strle F, Avsic-Zupanc T. Tick-borne encephalitis associated with consumption of raw goat milk, Slovenia, 2012. Emerg Infect Dis. 2013;19:806\u20138.","journal-title":"Emerg Infect Dis"},{"key":"1943_CR5","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1093\/infdis\/jix040","volume":"215","author":"D Lipowski","year":"2017","unstructured":"Lipowski D, Popiel M, Perlejewski K, Nakamura S, Bukowska-Osko I, Rzadkiewicz E, Dzieciatkowski T, Milecka A, Wenski W, Ciszek M, et al. A cluster of fatal tick-borne encephalitis virus infection in organ transplant setting. 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S. 1105; 25.05.1998) at the Helmholtz Center for Infection Research in Braunschweig. The mice were housed and handled in accordance with good animal practice as defined by FELASA. All animal experiments were approved by the Lower Saxony State Office of Consumer Protection and Food Safety under permit number AZ 33.19-42502-04-15\/1895. For primary cell isolation, mice were maintained under specific pathogen-free conditions and experiments were approved and carried out according to the guidelines set out by the regional animal ethical committee (Ume\u00e5, Sweden) under approval number A77-14. For the serological analysis, the research was carried out in line with \u201cThe Code of Ethics of the World Medical Association (Declaration of Helsinki)\u201d and according to good clinical practice guidelines. In accordance with local legislation, no formal approval by a research ethics committee was required, because either anonymous samples or sera for research purposes were used.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"284"}}