{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:39:08Z","timestamp":1791686348808,"version":"4.3.4"},"reference-count":105,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2018,6,16]],"date-time":"2018-06-16T00:00:00Z","timestamp":1529107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Tick-borne flaviviruses have a global distribution and cause significant human disease, including encephalitis and hemorrhagic fever, and often result in neurologic sequelae. There are two distinct properties that determine the neuropathogenesis of a virus. The ability to invade the central nervous system (CNS) is referred to as the neuroinvasiveness of the agent, while the ability to infect and damage cells within the CNS is referred to as its neurovirulence. Examination of laboratory variants, cDNA clones, natural isolates with varying pathogenicity, and virally encoded immune evasion strategies have contributed extensively to our understanding of these properties. Here we will review the major viral determinants of virulence that contribute to pathogenesis and influence both neuroinvasiveness and neurovirulence properties of tick-borne flaviviruses, focusing particularly on the envelope protein (E), nonstructural protein 5 (NS5), and the 3\u2032 untranslated region (UTR).<\/jats:p>","DOI":"10.3390\/v10060329","type":"journal-article","created":{"date-parts":[[2018,6,18]],"date-time":"2018-06-18T10:57:11Z","timestamp":1529319431000},"page":"329","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Viral Determinants of Virulence in Tick-Borne Flaviviruses"],"prefix":"10.3390","volume":"10","author":[{"given":"Eliza M.","family":"Kellman","sequence":"first","affiliation":[{"name":"Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT 59840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0736-1664","authenticated-orcid":false,"given":"Danielle K.","family":"Offerdahl","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT 59840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wessam","family":"Melik","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Orebro University, SE-703 62 \u00d6rebro, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marshall E.","family":"Bloom","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT 59840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/BF00145300","article-title":"Family outbreak of alimentary tick-borne encephalitis in Slovakia associated with a natural focus of infection","volume":"12","author":"Kohl","year":"1996","journal-title":"Eur. 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