| Tick-borne encephalitis virus | |
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| TBEV at different pH levels | |
Virus classification  | |
| (unranked): | Virus |
| Realm: | Riboviria |
| Kingdom: | Orthornavirae |
| Phylum: | Kitrinoviricota |
| Class: | Flasuviricetes |
| Order: | Amarillovirales |
| Family: | Flaviviridae |
| Genus: | Flavivirus |
| Species: | Tick-borne encephalitis virus |
| Strains | |
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Tick-borne encephalitis virus (TBEV) is a positive-strand RNA virus associated with tick-borne encephalitis in the genus Flavivirus .
TBEV is a member of the genus Flavivirus . Other close relatives, members of the TBEV serocomplex, include Omsk hemorrhagic fever virus , Kyasanur Forest disease virus , Alkhurma virus, Louping ill virus and Langat virus . [1]
TBEV has three subtypes:
The reference strain is the Sofjin strain. [3]
TBEV is a positive-sense single-stranded RNA virus, contained in a 40-60 nm spherical, enveloped capsid. [1] 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. [1] Like other flaviviruses, [4] the TBEV genome codes for ten viral proteins, three structural, and seven nonstructural. [5] [1]
The structural proteins are C (capsid), PrM (premembrane), which is cleaved to produce the final membrane protein, (M), and envelope protein (E). The seven nonstructural proteins are: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. The role of some nonstructural proteins is known, NS5 serves as RNA-dependent RNA polymerase, NS3 has protease (in complex with NS2B) and helicase activity. [5] [1] Structural and nonstructural proteins are not required for the genome to be infectious. [1] All viral proteins are expressed as a single large polyprotein, with the order C, PrM, E, NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5. [5]
The envelope protein is involved in receptor-binding and neurovirulence, where increased glycosaminoglycan-binding affinity attenuates neuroinvasiveness. [6] The conformation of the E protein during viral particle secretion is influenced by glycosylation as well. [7] 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. [8] 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. [6]
Infection of the vector begins when a tick takes a blood meal from an infected host. This can occur at any part of the tick's life cycle but a horizontal transmission between infected nymphs and uninfected larvae co-feeding on the same host is thought to be key in maintaining the circulation of TBEV. [9] [1] TBEV in the blood of the host infects the tick through the midgut, from where it can pass to the salivary glands to be passed to the next host. In non-adult ticks, TBEV is transmitted transtadially by infecting cells that are not destroyed during molting, thus the tick remains infectious throughout its life. [9] Infected adult ticks may be able to lay eggs that are infected, transmitting the virus transovarially. [10]
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. [5] TBEV envelope (E) proteins recognize heparan sulfate (and likely other receptors) on the host cell surface and are endocytosed via the clathrin mediated pathway. Acidification of the late endosome triggers a conformational change in the E proteins, resulting in fusion, followed by uncoating, and release of the single-stranded RNA genome into the cytoplasm. [11] [1]
The viral polyprotein is translated and inserts into the ER membrane, where it is processed on the cytosolic side by host peptidases and in the lumen by viral enzyme action. The viral proteins C, NS3, and NS5 are cleaved into the cytosol (though NS3 can complex with NS2B or NS4A to perform proteolytic or helicase activity), while the remaining nonstructural proteins alter the structure of the ER membrane. This altered membrane permits the assembly of replication complexes, where the viral genome is replicated by the viral RNA-dependent RNA polymerase, NS5. [11] [5]
Newly replicated viral RNA genomes are then packaged by the C proteins while on the cytosolic side of the ER membrane, forming the immature nucleocapsid, and gain E and PrM proteins, arranged as a heterodimer, during budding into the lumen of the ER. The immature virion is spiky and geometric in comparison to the mature particle. The particle passes through the golgi apparatus and trans-golgi network, under increasingly acidic conditions, by which the virion matures with cleavage of the Pr segment from the M protein and formation fusion competent E protein homodimers. Though the cleaved Pr segment remains associated with protein complex until exit. [1] [11]
The virus is released from the host cell upon fusion of the transport vesicle with the host cell membrane, the cleaved Pr now segments dissociate, resulting in a fully mature, infectious virus. [1] [11] However, partially mature and immature viruses are sometimes released as well; immature viruses are noninfectious as the E proteins are not fusion competent, partially mature viruses are still capable of infection. [11]
With the exception of food-borne cases, infection begins in the skin at the site of the tick bite. Skin dendritic (or Langerhans) cells (DCs) are preferentially targeted. [5] Initially, the virus replicates locally and immune response is triggered when viral components are recognized by cytosolic pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs). [12] 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. [5] The infection may be halted at this stage and cleared, before the onset of noticeable symptoms. Notably, tick saliva enhances infection by modulating host immune response, dampening apoptotic signals. [12] If the infection continues, migratory DCs and macrophages become infected and travel to the local draining lymph node where activation of polymorphonuclear leukocytes, monocytes and the complement system are activated. [12]
The draining lymph node can also serve as a viral amplification site, from where TBEV gains systemic access. This viremic stage corresponds to the first symptomatic phase in the prototypical biphasic pattern of tick-borne encephalitis. [1] TBEV has a strong preference for neuronal tissue, and is neuroinvasive. [13] The initial viremic stage allows access to a number of the preferential tissues. However, the exact mechanism by which TBEV crosses into the central nervous system (CNS) is unclear. [13] [12] [1] There are several proposed mechanism for TBEV breaching the blood-brain barrier (BBB): 1)The "Trojan Horse" mechanism, whereby TBEV gains access to the CNS while infecting an immune cell that passes through the BBB; [12] [5] [13] 2) Disruption and increased permeability of the BBB by immune immune cytokines; [13] 3) Via infection of the olfactory neurons; [5] 4) Via retrograde transport along peripheral nerves to the CNS; [5] 5) Infection of the cells that make up part of the BBB. [5] [12]
CNS infection brings on the second phase in the classic biphasic infection pattern associated with the European subtype. CNS disease is immunopathological; release of inflammatory cytokines coupled with the action of cytotoxic CD8+ T cells and possibly NK cells results in inflammation and apoptosis of infected cells that is responsible for many of the CNS symptoms. [12] [13]
TBEV specific IgM and IgG antibodies are produced in response to infection. [1] IgM antibodies appear and peak first, as well as reaching higher levels, and typically dissipate in about 1.5 months post infection, though there exists considerable variation from patient to patient. IgG levels peak at about 6 weeks after the appearance of CNS symptoms, then decline slightly but do not dissipate, likely conferring life long immunity to the patient. [1] [5]
The ancestor of the extant strains appears to have separated into several clades approximately 2750 years ago. [14] 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. [15] Different strains of the virus have been transmitted at least three times into Japan between 260–430 years ago. [16] [17] The strains circulating in Latvia appear to have originated from both Russia and Western Europe [18] while those in Estonia appear to have originated in Russia. [19] The Lithuanian strains appear to be related to those from Western Europe. [20] 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. [1] However, in antigenic relatedness, based on the E, NS3, and NS5 proteins, all three sub-types are highly similar, and Louping Ill virus is the closest relative outside the collective TBEV group. [21]
Though the first description of what may have been TBE appears in records in the 1700s in Scandinavia, [13] identification of the TBEV virus occurred in the Soviet Union in the 1930s. [22] 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. [23] [22] The expedition arrived in Khabarovsk on May 15, 1937, and divided into squads, Northern-led by Elizabeth N. Levkovich and working in the Khabarovski Krai- and Southern-led by Alexandra D. Sheboldaeva, working in the Primorski Krai. [22]
Inside the month of May, the expedition had identified ticks as the likely vector, collected I. persucatus ticks by exposure of bare skin by entomologist Alexander V. Gutsevich and virologist Mikhail P. Chumakov had isolated the virus from ticks feeding on intentionally infected mice. During the summer, five expeditions members became infected with TBEV, and while there were no fatalities, three of the five suffered damaging sequelae. [22]
The expedition returned in mid-August and in October 1937 Zilber and Sheboldova were arrested, falsely accused of spreading Japanese encephalitis. Expedition epidemiologist Tamara M. Safonov, was arrested the following January for protesting the charges against Zilber and Sheboldova. As a consequence of the arrests, one of the important initial works was published under the authorship of expedition acarologist, Vasily S. Mironov. Zilber was released in 1939 and managed to restore, along with Sheboldova, co-authorship on this initial work; however, Safanov and Sheboldova (who was not released) spent 18 years in labor camps. [22] [23]
Flaviviridae is a family of enveloped positive-strand RNA viruses which mainly infect mammals and birds. They are primarily spread through arthropod vectors. The family gets its name from the yellow fever virus; flavus is Latin for "yellow", and yellow fever in turn was named because of its propensity to cause jaundice in victims. There are 89 species in the family divided among four genera. Diseases associated with the group include: hepatitis (hepaciviruses), hemorrhagic syndromes, fatal mucosal disease (pestiviruses), hemorrhagic fever, encephalitis, and the birth defect microcephaly (flaviviruses).
Flavivirus, renamed Orthoflavivirus in 2023, is a genus of positive-strand RNA viruses in the family Flaviviridae. The genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus and several other viruses which may cause encephalitis, as well as insect-specific flaviviruses (ISFs) such as cell fusing agent virus (CFAV), Palm Creek virus (PCV), and Parramatta River virus (PaRV). While dual-host flaviviruses can infect vertebrates as well as arthropods, insect-specific flaviviruses are restricted to their competent arthropods. The means by which flaviviruses establish persistent infection in their competent vectors and cause disease in humans depends upon several virus-host interactions, including the intricate interplay between flavivirus-encoded immune antagonists and the host antiviral innate immune effector molecules.
The hepatitis C virus (HCV) is a small, enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer and lymphomas in humans.
Dengue virus (DENV) is the cause of dengue fever. It is a mosquito-borne, single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus. Four serotypes of the virus have been found, and a reported fifth has yet to be confirmed, all of which can cause the full spectrum of disease. Nevertheless, the mainstream scientific community's understanding of dengue virus may be simplistic as, rather than distinct antigenic groups, a continuum appears to exist. This same study identified 47 strains of dengue virus. Additionally, coinfection with and lack of rapid tests for Zika virus and chikungunya complicate matters in real-world infections.
Bunyavirales is an order of segmented negative-strand RNA viruses with mainly tripartite genomes. Member viruses infect arthropods, plants, protozoans, and vertebrates. It is the only order in the class Ellioviricetes. The name Bunyavirales derives from Bunyamwera, where the original type species Bunyamwera orthobunyavirus was first discovered. Ellioviricetes is named in honor of late virologist Richard M. Elliott for his early work on bunyaviruses.
Japanese encephalitis (JE) is an infection of the brain caused by the Japanese encephalitis virus (JEV). While most infections result in little or no symptoms, occasional inflammation of the brain occurs. In these cases, symptoms may include headache, vomiting, fever, confusion and seizures. This occurs about 5 to 15 days after infection.
The term viral protein refers to both the products of the genome of a virus and any host proteins incorporated into the viral particle. Viral proteins are grouped according to their functions, and groups of viral proteins include structural proteins, nonstructural proteins, regulatory proteins, and accessory proteins. Viruses are non-living and do not have the means to reproduce on their own, instead depending on their host cell's machinery to do this. Thus, viruses do not code for most of the proteins required for their replication and the translation of their mRNA into viral proteins, but use proteins encoded by the host cell for this purpose.
Tick-borne encephalitis (TBE) is a viral infectious disease involving the central nervous system. The disease most often manifests as meningitis, encephalitis or meningoencephalitis. Myelitis and spinal paralysis also occurs. In about one third of cases sequelae, predominantly cognitive dysfunction, persist for a year or more.
Alphavirus is a genus of RNA viruses, the sole genus in the Togaviridae family. Alphaviruses belong to group IV of the Baltimore classification of viruses, with a positive-sense, single-stranded RNA genome. There are 32 alphaviruses, which infect various vertebrates such as humans, rodents, fish, birds, and larger mammals such as horses, as well as invertebrates. Alphaviruses that could infect both vertebrates and arthropods are referred dual-host alphaviruses, while insect-specific alphaviruses such as Eilat virus and Yada yada virus are restricted to their competent arthropod vector. Transmission between species and individuals occurs mainly via mosquitoes, making the alphaviruses a member of the collection of arboviruses – or arthropod-borne viruses. Alphavirus particles are enveloped, have a 70 nm diameter, tend to be spherical, and have a 40 nm isometric nucleocapsid.
Thogotovirus is a genus of enveloped RNA viruses, one of seven genera in the virus family Orthomyxoviridae. Their single-stranded, negative-sense RNA genome has six or seven segments. Thogotoviruses are distinguished from most other orthomyxoviruses by being arboviruses – viruses that are transmitted by arthropods, in this case usually ticks. Thogotoviruses can replicate in both tick cells and vertebrate cells; one subtype has also been isolated from mosquitoes. A consequence of being transmitted by blood-sucking vectors is that the virus must spread systemically in the vertebrate host – unlike influenza viruses, which are transmitted by respiratory droplets and are usually confined to the respiratory system.
Orbivirus is a genus of double-stranded RNA viruses in the family Reoviridae and subfamily Sedoreovirinae. Unlike other reoviruses, orbiviruses are arboviruses. They can infect and replicate within a wide range of arthropod and vertebrate hosts. Orbiviruses are named after their characteristic doughnut-shaped capsomers.
Pestivirus is a genus of viruses, in the family Flaviviridae. Viruses in the genus Pestivirus infect mammals, including members of the family Bovidae and the family Suidae. There are 11 species in this genus. Diseases associated with this genus include: hemorrhagic syndromes, abortion, and fatal mucosal disease.
Tick-borne encephalitis vaccine is a vaccine used to prevent tick-borne encephalitis (TBE). The disease is most common in Central and Eastern Europe, and Northern Asia. More than 87% of people who receive the vaccine develop immunity. It is not useful following the bite of an infected tick. It is given by injection into a muscle.
Spondweni virus is an arbovirus, or arthropod-borne virus, which is a member of the family Flaviviridae and the genus Flavivirus. It is part of the Spondweni serogroup which consists of the Sponweni virus and the Zika virus (ZIKV). The Spondweni virus was first isolated in Nigeria in 1952, and ever since, SPONV transmission and activity have been reported throughout Africa. Its primary vector of transmission is the sylvatic mosquito Aedes circumluteolus, though it has been isolated from several different types of mosquito. Transmission of the virus into humans can lead to a viral infection known as Spondweni fever, with symptoms that include headache, nausea, myalgia and arthralgia. However, as SPONV is phylogenetically close to the ZIKV, it is commonly misdiagnosed as ZIKV along with other viral illnesses.
West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family Flaviviridae, from the genus Flavivirus, which also contains the Zika virus, dengue virus, and yellow fever virus. The virus is primarily transmitted by mosquitoes, mostly species of Culex. The primary hosts of WNV are birds, so that the virus remains within a "bird–mosquito–bird" transmission cycle. The virus is genetically related to the Japanese encephalitis family of viruses. Humans and horses both exhibit disease symptoms from the virus, and symptoms rarely occur in other animals.
Yokose virus (YOKV) is in the genus Flavivirus of the family Flaviviridae. Flaviviridae are often found in arthropods, such as mosquitoes and ticks, and may also infect humans. The genus Flavivirus includes over 50 known viruses, including Yellow Fever, West Nile Virus, Zika Virus, and Japanese Encephalitis. Yokose virus is a new member of the Flavivirus family that has only been identified in a few bat species. Bats have been associated with several emerging zoonotic diseases such as Ebola and SARS.
Sepik virus (SEPV) is an arthropod-borne virus (arbovirus) of the genus Flavivirus and family Flaviviridae. Flaviviridae is one of the most well characterized viral families, as it contains many well-known viruses that cause diseases that have become very prevalent in the world, like Dengue virus. The genus Flavivirus is one of the largest viral genera and encompasses over 50 viral species, including tick and mosquito borne viruses like Yellow fever virus and West Nile virus. Sepik virus is much less well known and has not been as well-classified as other viruses because it has not been known of for very long. Sepik virus was first isolated in 1966 from the mosquito Mansoniaseptempunctata, and it derives its name from the Sepik River area in Papua New Guinea, where it was first found. The geographic range of Sepik virus is limited to Papua New Guinea, due to its isolation.
Modoc virus (MODV) is a rodent-associated flavivirus. Small and enveloped, MODV contains positive single-stranded RNA. Taxonomically, MODV is part of the Flavivirus genus and Flaviviridae family. The Flavivirus genus includes nearly 80 viruses, both vector-borne and no known vector (NKV) species. Known flavivirus vector-borne viruses include Dengue virus, Yellow Fever virus, tick-borne encephalitis virus, and West Nile virus.
Rio Negro virus is an alphavirus that was first isolated in Argentina in 1980. The virus was first called Ag80-663 but was renamed to Rio Negro virus in 2005. It is a former member of the Venezuelan equine encephalitis complex (VEEC), which are a group of alphaviruses in the Americas that have the potential to emerge and cause disease. Río Negro virus was recently reclassified as a distinct species. Closely related viruses include Mucambo virus and Everglades virus.
Christian Kunz was an Austrian virologist known for his work on the development of vaccines against tick-borne encephalitis, and his contributions to viral diagnostics and medical virology in Austria and Europe.
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