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Virology
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. Like other flaviviruses, 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 withwith NS2B) and helicase activity. Structural and nonstructral proteins are not required for the genome to be infectious. All viral proteins are expressed as a single large polyprotein, with the order C, PrM, E, NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5.

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. 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. Infected adult ticks may be able to lay eggs that are infected, transmitting the virus transorvarially.

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. 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 the late endosome triggers a conformational change in the the E proteins, resulting in fusion, followed by uncoating, and release of the single-stranded RNA genome into the cytoplasm. 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 the viral genome is replicated by the viral RNA-dependent polymerase, NS5. 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 the cleaved Pr segment remains associated with protein complex until exit. 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. 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.

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. 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). 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. 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. 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.

The draining lymph node can also serve as a viral amplification site, from where TBEV gains systemic access. This viremic stage corresponds to the the first symptomatic phase in the prototypical biphasic pattern of tick-borne encephalitis. TBEV has a strong preference for neuronal tissue, and is neuroinvasive. 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. 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  ; 2) Disruption and increased permeability of the BBB by immune immune cytokines ; 3) Via infection of the olfactory neurons ; 4) Via retrograde transport along peripheral nerves to the CNS ; 5) Infection of the cells that make up part of the BBB.

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.

Humoral reponse
TBEV specific IgM and IgG antibodies are produced in response to infection. 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.

= Orthobunyaviruses =

Vectors
The primary vectors of Orthobunyaviruses are hematophagous insects of the Culicidae family, including members from a number of mosquito genera (including Aedes, Coquillettidia, Culex, Culiseta, and Anopheles) and biting midges (such as Culicoides paraensis). Although transmission by ticks and bed bugs may also occur. Viral vector preference is generally strict, with only a one or very small number of vectors transmitting a specific virus in the region, even where multiple viruses and vectors overlap. Organisms related to the preferential vector may be able to carry a virus but not competently transmit it.

The vector arthropod acquires the virus while taking a blood meal from an infected host. In mosquitoes, replication of orthobunyaviruses is enhanced by immune modulation that occurs as a result of blood protein digestion producing GABA and the activation of GABAergic signalling. Infection is transmitted to a new host via viral particles in vector saliva. Orthobunyavirus infection in arthropod cells is not fully understood, but is generally non-cytopathological and deleterious effects are minimal. Infected mosquitoes may experience an increase in fitness. Transorvarial transmission has been observed among mosquitoes infected with orthobunyaviruses of the California serogroup Like mosquitoes, only female culicoid midges feed on blood; they prefer indoor feeding particularly during rain.

Sylvatic Cycle Hosts
In the slyvatic cycle, viruses are transmitted between mammalian hosts by the arthropod vector. A diverse range of mammals have been identified or implicated as hosts or reservoirs of orthobunyaviruses including: non-human primates, sloths, wild and domestic birds, marmosets, rodents, and large mammals such as deer, moose, and elk.

Infection
Infection begins with the bite of an infected competent vector organism. Viral entry proceeds by receptor-mediated (clathrin-dependent) endocytosis, but which receptors unknown. Although, Heparan sulfate and DC-SIGN (CD209 or Dendritic cell-specific intracellular adhesion molecule-3-grabbing non-integrin) have been identified as viral entry components in some orthobunyaviruses. Gn/Gc heterodimers on the viral surface are responsible for target cell recognition, with Gc is considered the primary attachment protein, although Gn has been suggested as the attachment protein for LACV in arthropod cells. Acidification of the endosome triggers a conformational change in the Gc fusion peptide, uncoating the ribonuclearprotein (RNP) as it is released into the cytoplasm.

Upon release into the cytoplasm, primary transcription begins with an endonuclease domain on L protein engaging in a process known as "cap-snatching." During cap-snatching, 10-18 nucleotides of 5' 7-methylguanylate primers are cleaved from host mRNAs and attached to prime the 5' end of the viral RNAs. Like all negative-sense RNA viruses, orthobunyaviruses require ongoing, concurrent translation by the host cell to produce full-length viral mRNAs, consequently the 3' end of orthobunyavirus mRNAs lack polyadenylation. Notably they are also missing the signal for for polyadenylation; instead the 3' ends are thought to form a stem-loop structure. Antigenomes (full length positive-sense RNAs) used as templates for replication of the viral genome are produced by L protein RdRp without the need for primers. Both negative-sense genomes and positive-sense antigenomes are associated with N proteins (forming RNPs) at all times during the replication cycle. Thus, N and L are the minimum proteins required for transcription and replication

The M genome segment codes for the Gn-NSm-Gc polyprotein on a single open-reading frame (ORF) which is cotranslationally cleaved by internal signal peptides and host signal peptidase. The free glycoproteins Gc and Gn insert into the membrane of the endoplasmic reticulum and form heterodimers. A Golgi retention signal on Gn, permits transport of the heterodimers to the Golgi apparatus, where glycosylation occurs. The presence of the viral glycoproteins modifies the Golgi membrane to enable budding of RNPs into a Golgi derived tubular viral factory (viroplasm). As segmented viruses, orthobuynaviruses require precise packaging of one of each of the three genomic segments into the final virion to produce a mature, infectious particle. Packaging appears to be directed by signals contained entirely within UTR sequences. The packaged genomes acquire a lipid membrane as they bud into the viral factories, are then transported to the host cell plasma membrane and released via exocytosis. A final gylcoprotein modification upon release produces a mature, infectious particle.