Tick-borne encephalitis virus

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Tick-borne encephalitis virus
Tick-Borne Encephalitis Virus.png
TBEV at different pH levels
Virus classification Red Pencil Icon.png
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Kitrinoviricota
Class: Flasuviricetes
Order: Amarillovirales
Family: Flaviviridae
Genus: Flavivirus
Species:
Tick-borne encephalitis virus

Tick-borne encephalitis virus (TBEV) is a virus associated with tick-borne encephalitis.

Contents

Taxonomy

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]

Subtypes

TBEV has three subtypes:

The reference strain is the Sofjin strain. [3]

Virology

TBEV is a positive-sense single stranded RNA virus, contained in a 40-60 nm spherical, enveloped capsid. [4] 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. [4] Like other flaviviruses, [5] the TBEV genome codes for ten viral proteins, three structural, and seven nonstructural (NS). The structural proteins are C (capsid), PrM (premembrane, which is cleaved to produce the final membrane protein, M), and E (envelope). 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 polymerase, NS3 has protease (in complex with NS2B) and helicase activity. [6] [4] Structural and nonstructral proteins are not required for the genome to be infectious. [4] All viral proteins are expressed as a single large polyprotein, with the order C, PrM, E, NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5. [6]

Life cycle

Vector

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. [7] [4] 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. [7] Infected adult ticks may be able to lay eggs that are infected, transmitting the virus transorvarially. [8]

Viral

In humans, the infection begins in the skin (with the exception of foodborne 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. [6] 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. [9] [4] 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 polymerase, NS5. [9] [6] Newly replicated viral RNA genomes are then packaged by the C proteins while on the cytosolic side of the of the ER memebrane, 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. [4] [9] 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. [4] [9] 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. [9]

Pathogenesis and immune response

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. [6] 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). [10] 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. [6] 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. [10] 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. [10]

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. [4] TBEV has a strong preference for neuronal tissue, and is neuroinvasive. [11] 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. [11] [10] [8] [4] 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; [10] [6] [11] 2) Disruption and increased permeability of the BBB by immune immune cytokines; [11] 3) Via infection of the olfactory neurons; [6] 4) Via retrograde transport along peripheral nerves to the CNS; [6] 5) Infection of the cells that make up part of the BBB. [6] [10]

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. [10] [11]

Humoral response

TBEV specific IgM and IgG antibodies are produced in response to infection. [4] IgM antibodies appear and peak first, as well as reaching higher levels, and typically dissipates 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. [4] [6]

Evolution

The ancestor of the extant strains appears to have separated into several clades approximately 2750 years ago. [12] 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 ~300 years ago. [13]

This virus has been transmitted at least three times into Japan between 260–430 years ago. [14] [15]

The strains circulating in Latvia appear to have originated from both Russia and Western Europe [16] while those in Estonia appear to have originated in Russia. [17] The Lithuanian strains appear to be related to those from Western Europe. [18]

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. [19]

History

Though the first description of what may have been TBE appears in records in the 1700s in Scandinavia, [11] identification of the TBEV virus occurred in the Soviet Union in the 1930s. [20] 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 lead 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. [21] [20] 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. [20]

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. [20]

The expedition returned in mid August and in October of 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, the 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. [20] [21]

Related Research Articles

<i>Flavivirus</i> Genus of viruses

Flavivirus is a genus of viruses in the family Flaviviridae. This 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).

<i>Human orthopneumovirus</i> Species of virus

Human orthopneumovirus is a virus that causes respiratory tract infections, with the infected cells of the mucosa fusing together to form a syncytium. It is a major cause of lower respiratory tract infections and hospital visits during infancy and childhood. A prophylactic medication, palivizumab, can be employed to prevent HRSV in preterm infants, infants with certain congenital heart defects (CHD) or bronchopulmonary dysplasia (BPD), and infants with congenital malformations of the airway. Treatment is limited to supportive care, including oxygen therapy and more advanced breathing support with CPAP or nasal high flow oxygen, as required.

Hepatitis C virus Species of virus

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.

<i>Dengue virus</i> cause of dengue fever

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. Five serotypes of the virus have been found, all of which can cause the full spectrum of disease. Nevertheless, scientists' 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.

<i>Bunyavirales</i> Order of negative-sense single-stranded RNA viruses

Bunyavirales is an order of negative-sense single-stranded RNA viruses. It is the only order in the class Ellioviricetes. It was formerly known as Bunyaviridae family of viruses. 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 Infection of the brain caused by the Japanese encephalitis virus

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.

Viral protein proteins found in any species of virus

A viral protein is both a component and a product of a virus. 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 they do not have the means to reproduce on their own. They depend on their host cell's metabolism for energy, enzymes, and precursors, in order to reproduce. Thus, viruses do not code for many of their own viral proteins, and instead use the host cell's machinery to produce the viral proteins they require for replication.

<i>Alphavirus</i> Genus of viruses

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 31 alphaviruses, which infect various vertebrates such as humans, rodents, fish, birds, and larger mammals such as horses, as well as invertebrates. 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.

<i>Thogotovirus</i> genus of viruses

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.

Powassan virus (POWV) is a Flavivirus transmitted by ticks, found in North America and in the Russian Far East. It is named after the town of Powassan, Ontario, where it was identified in a young boy who eventually died from it. It can cause encephalitis, an infection of the brain. No vaccine or antiviral drug exists. Prevention of tick bites is the best precaution.

Rice hoja blanca tenuivirus (RHBV), meaning "white leaf rice virus", is a plant virus in the family Phenuiviridae. RHBV causes Hoja blanca disease (HBD), which affects the leaves of the rice plant Oryza sativa, stunting the growth of the plant or killing it altogether. RHBV is carried by an insect vector, Tagosodes orizicolus, a type of planthopper. The virus is found in South America, Mexico, throughout Central America, the Caribbean region, and the southern United States. In South America, the disease is endemic to Colombia, Venezuela, Ecuador, Peru, Suriname, French Guiana and Guyana.

NSP1, the product of rotavirus gene 5, is a nonstructural RNA-binding protein that contains a cysteine-rich region and is a component of early replication intermediates. RNA-folding predictions suggest that this region of the NSP1 mRNA can interact with itself, producing a stem-loop structure similar to that found near the 5'-terminus of the NSP1 mRNA.

Minute virus of mice

Minute virus of mice (MVM) is the exemplar virus of the type species, Rodent protoparvovirus 1, in the genus Protoparvovirus of the Parvoviridae family of viruses. MVM exists in multiple variant forms including MVMp, which is the prototype strain that infects cells of fibroblast origin, while MVMi, the immunosuppressive strain, infects T lymphocytes. MVM is a common infection in laboratory mice due to its highly contagious nature. The virus can be shed from infected mice via feces and urine, but also via fomites and nasal secretions. Typically there are no clinical signs of infection in adult mice, however, experimental infection can cause multiple organ damage during fetal development or shortly after birth.

Tahyna orthobunyavirus ("TAHV") is a viral pathogen of humans classified in the California encephalitis virus (CEV) serogroup of the Orthobunyavirus family in the order Bunyavirales, which is endemic to Europe, Asia, Africa and possibly China.

Batai orthobunyavirus (BATV) is a RNA virus belonging to order Bunyavirales, genus Orthobunyavirus.

Epizootic hemorrhagic disease virus, often abbreviated to EHDV, is a species of the genus Orbivirus, a member of the family Reoviridae. It is the causative agent of epizootic hemorrhagic disease, an acute, infectious, and often fatal disease of wild ruminants. In North America, the most severely affected ruminant is the white-tailed deer, although it may also infect mule deer, black-tailed deer, elk, bighorn sheep, and pronghorn antelope. It is often mistakenly referred to as “bluetongue virus” (BTV), another Orbivirus that like EHDV causes the host to develop a characteristic blue tongue due to systemic hemorrhaging and lack of oxygen in the blood. Despite showing clinical similarities, these two viruses are genetically distinct.

<i>West Nile virus</i> Species of virus

West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family Flaviviridae, specifically from the genus Flavivirus, which also contains the Zika virus, dengue virus, and yellow fever virus. West Nile 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.

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.

<i>Sepik virus</i> Mosquito transmitted virus endemic to Papua New Guinea

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 Chikungunya virus and 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.

<i>Modoc virus</i> Species of virus

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.

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