Tick-borne encephalitis virus (TBEV) is an enveloped positive-strand RNA virus in the genus Orthoflavivirus that causes tick-borne encephalitis. TBEV is primarily transmitted to humans through infected ticks of the Ixodes species and can cause severe neurological diseases.

Classification

Resolving the paraphyletic issue of TBEV and LIV

TBEV is a group of viruses represented by two virus species: Orthoflavivirus zilberi and Orthoflavivirus neudoerflense. For a long time, TBEV was a member of the eponymous paraphyletic species Tick-borne encephalitis virus. The paraphyly was due to the European subtype of TBEV, which is phylogenetically closer to the louping-ill virus (LIV) than to the other TBEV subtypes.

In February 2026, the ICTV ratified a taxonomy proposal resolving the paraphyletic issue and untangling TBEV and LIV. According to this proposal, the European subtype of TBEV (a monophyletic clade) was assigned as a separate species—O. neudoerflense (after Neudörfl, a town in Austria where the prototype strain Neudoerfl was isolated). The remaining TBEV subtypes as a monophyletic clade were assigned as O. zilberi, after Lev A. Zilber—the leader of the Soviet expedition to the Far East of the USSR that resulted in the discovery and first isolation of TBEV.

Subtypes

TBEV has three subtypes:

  • Western European subtype (formerly Central European encephalitis virus, CEEV; principal tick vector: Ixodes ricinus);
  • Siberian subtype (formerly West Siberian virus; principal tick vector: Ixodes persulcatus);
  • Far Eastern subtype (formerly Russian Spring Summer encephalitis virus, RSSEV; principal tick vector: Ixodes persulcatus).

The reference strain is the Sofjin strain.

Virology

Structure

TBEV is a positive-sense single-stranded RNA virus, contained in a 40-60 nm spherical, enveloped capsid. The TBEV genome is approximately 11kb in size, which contains a 5' cap, a single open reading frame with 3' and 5' UTRs, and is without polyadenylation. the TBEV genome codes for ten viral proteins, three structural, and seven nonstructural. The conformation of the E protein during viral particle secretion is influenced by glycosylation as well. The immunogenicity of TBEV NS1 has been demonstrated, showcasing its ability to trigger oxidative stress and elicit the expression of immunoproteasome subunits. Additionally, it has been observed to stimulate the production of cytokines. The NS5 protein has interferon antagonist activity as it downregulates the expression of IFN receptor subunit. Non structural protein 5 (NS5) affects neuropathogenesis by attenuation of neurite outgrowth. Untranslated region 3 (UTR3) and UTR 5 affect genomic RNA cyclization and replication, and viral RNA transport in dendrites, which impacts neurogenesis and synaptic communication.

Replication

thumb|Replication cycle of tick-borne flaviviruses.

In humans, the infection begins in the skin (with the exception of food-borne cases, about 1% of infections) at the site of the bite of an infected tick, where Langerhans cells and macrophages in the skin are preferentially targeted. Recognition causes the release of cytokines including interferons (IFN) α, β, and γ and chemokines, attracting migratory immune cells to the site of the bite. TBEV primarily infects the cells in the cerebral cortex and cerebellum, showing a strong preference especially towards Purkinje cells. The infection of the neurons activates microglia in the brain. The Siberian and Far Eastern subtypes diverged about 2250 years ago. A second analysis suggests an earlier date of evolution (3300 years ago) with a rapid increase in the number of strains starting around 300 years ago. Different strains of the virus have been transmitted at least three times into Japan between 260–430 years ago. The strains circulating in Latvia appear to have originated from both Russia and Western Europe while those in Estonia appear to have originated in Russia. The Lithuanian strains appear to be related to those from Western Europe. Phylogenetic analysis indicates that the European and Siberian TBEV sub-types are closely related while the Far-eastern sub-type is closer to the Louping Ill Virus.

History

Though the first description of what may have been TBE appears in records in the 1700s in Scandinavia, The investigation began due to an outbreak of what was believed to be Japanese Encephalitis ("Summer encephalitis"), among Soviet troops stationed along the border with the Japanese empire (present day People's Republic of China), near the Far Eastern city of Khabarovsk. The expedition was led by virologist Lev A. Zilber, who assembled a team of twenty young scientists in a number of related fields such as acarology, microbiology, neurology, and epidemiology.