Thogotovirus

The genome encodes 7–9 proteins, including the trimeric RNA polymerase enzyme (PA, PB1, PB2) and the structural proteins nucleoprotein (NP), which binds the viral genome; matrix protein (M1), which lines the envelope; and an envelope glycoprotein (GP), which acts as the virus receptor.[15][16]

The thogotovirus glycoprotein is not similar to the influenza virus glycoproteins (haemagglutinin and neuraminidase), and instead shows some similarities with the gp64 glycoprotein of baculoviruses, which infect insects.[4][15][20] It also has some similarity with the haemagglutinin of Quaranfil virus of the related genus of tick-transmitted orthomyxoviruses Quaranjavirus.[21] The mechanism by which thogotoviruses gained a baculovirus-like glycoprotein is unknown. Pat Nuttall and colleagues have speculated that the acquisition enabled these viruses to infect ticks.[22] This apparent receptor specificity for arthropod cells does not prevent most thogotoviruses from infecting vertebrates.[15] The thogotovirus glycoprotein is classified as a class III or γ penetrene, lacking the fusion peptide present in influenza haemagglutinin (a class I or α penetrene).[23]

THOV and JOSV[2] also encode the protein M-long (ML), which counters the host's innate immunity, in particular by suppressing the production of interferon. This immune evasion is important for the virus to infect systemically in vertebrates, but is unnecessary in arthropods, which lack the interferon response. The mechanism of action of ML is completely different from the equivalent protein in influenza viruses (NS1).[15][16][24][25]

As in all orthomyxoviruses, the largest three segments (1–3) encode the three subunits of the RNA polymerase. In thogotoviruses, segment 4 encodes the glycoprotein and segment 5 the nucleoprotein. The messenger RNA (mRNA) from segment 6 can be spliced to encode the matrix protein or unspliced to encode ML, which has 38 additional amino acids at its C-terminus.[4][15][16][18] No product has yet been identified for the seventh segment, observed in DHOV.[18]

Electron micrograph showing endocytosis (arrows) of Bourbon virus (scale bar: 100 nm)

The receptor on the vertebrate host cell is sialic acid, which is bound by the viral glycoprotein. Entry is by endocytosis, with fusion of the viral and cell membranes occurring once the vesicle is acidified. In common with other orthomyxoviruses, viral transcription and replication both occur in the cell nucleus.[15][16] In some members of the genus, replication has been shown to be sensitive to the Mx1/MxA protein, which is induced in mice and humans in response to interferon.[9][26] In one study, this inhibitory effect was shown to be caused by MxA preventing the transport of the THOV genome into the nucleus.[27]

As orthomyxoviruses do not encode a capping enzyme, initiation of transcription involves the virus cutting the cap off the 5′-end of host mRNAs, so that the mRNA is recognised by the host translation machinery. A similar "cap snatching" process is used by other orthomyxoviruses, but a much longer host RNA sequence is cleaved along with the cap and incorporated into the viral mRNA.[28][29]

The virus assembles by the cell membrane and leaves the cell by budding.[16] For THOV grown in baby hamster kidney cells, virus particles start to be released 6–8 hours after infection, with substantial quantities still being produced 24 hours after infection. This growth rate is slower than that of influenza viruses, and is more similar to Quaranfil virus.[17][21]

No major pathological changes are observed in Rhipicephalus appendiculatus ticks infected with THOV.[17] The virus is concentrated in the synganglion (the tick brain) early on in the blood-feeding process, with the proportion of virus located in the salivary glands increasing during the late phase of blood-feeding.[17][33] Lower levels of virus are found in the trachea, digestive tract and female sex organs, but not in the male sex organs or the excretory system. The high level of virus present in the synganglion has been proposed to help the virus persist through the metamorphosis of the tick, as the nervous system undergoes less remodeling than other systems.[17]

In the laboratory setting, several members of the genus cause severe disease in mice and hamsters.[5][6] Systemic spread of the virus occurs, with pathological effects present in multiple organs and systems, including the brain, liver, lymphatic system, and sometimes the lungs and small intestine.[5][6] Lymphocytes are a major target cell for DHOV.[6] DHOV infection in mice resembles experimental influenza infection in mice and ferrets as well as fatal H5N1 influenza infection of humans, and has been proposed as a model for this disease.[6]

Natural infections with thogotoviruses in mammals generally do not appear to result in symptoms. THOV is a significant veterinary pathogen, for example, causing a febrile illness and abortion in sheep.[5][36][37][38][39] As of February 2015, only eight cases of human disease associated with thogotoviruses have been reported: two with THOV, five with DHOV and one with Bourbon virus; there have been two fatalities.[7] The incubation period for THOV is 4–5 days.[39] All three viruses were associated with fever. THOV and DHOV also caused neurological symptoms: meningitis and neuromyelitis optica in the case of THOV; encephalitis in the case of DHOV.[7][8][13][39] Hepatitis has been observed with THOV.[39] The single case of disease in a person infected with Bourbon virus was associated with decreases in blood platelets and white cells; no neurological symptoms were observed.[7] Influenza-like respiratory symptoms have not been reported.[7][8]

THOV was first isolated from ticks gathered from cattle in the Thogoto Forest region of Kenya, near Nairobi, in 1960,[5] it is now known to be distributed across the African continent, and has also been found in Italy and Portugal in Europe, and Iran in the Middle East.[19][31][44] Despite this wide geographical range, the virus shows only limited variation.[44] Its vectors include various hard-bodied ticks, including Amblyomma, Hyalomma and Rhipicephalus species.[5][13][19][31][45]

Antibodies have been found to THOV in rats and many domestic animals, including goats, sheep, donkeys, camels, cattle and buffaloes, and the virus has been isolated from the wild banded mongoose (Mongos mungo).[13][32] It causes significant livestock disease, including a febrile illness and abortion in sheep.[5][36][37][38] In artificial laboratory infections, it is highly pathogenic in hamsters and also infects mice.[5] The virus is known to infect humans in natural settings.[7][31]

The virus particle is generally spherical with some filamentous forms; the diameter is around 100 nm.[17] The genome has six RNA segments.[4]

The Araguari virus was first isolated from a Gray four-eyed opossum (Philander opossum) in Serra do Navio, Amapá, Brazil in 1969.[14] Its method of transmission is unknown.[6] In laboratory infections, it is pathogenic to mice. The virion is around 105 nm in diameter. The genome has six RNA segments. Based on partial sequence data the virus was found to be most closely related to THOV.[14]

ABV was found in the soft-bodied tick genus Ornithodoros in seabird nests in southern Texas, USA, in 1975; it was the first member of the genus to be found in North America.[7][15] No natural vertebrate host has been identified, but the virus is highly pathogenic to mice in laboratory infections. The virus particle is spherical or ovoid, with a range of sizes, from 75 nm × 85 nm to 120 nm × 140 nm. The genome has six RNA segments. It is most similar to UPOV, with some similarity to THOV and JOSV.[15]

Hyalomma marginatum is one of the vectors of DHOV

JOSV was first isolated from the zebu (Bos indicus) in Jos, Nigeria in 1967. It has since been found infecting Amblyomma and Rhipicephalus hard-bodied ticks in several countries across Africa. In the laboratory it causes severe pathology in mice. The virus particle has a variable, usually ovoid, morphology with a diameter of 85–120 nm. The genome contains at least six RNA segments.[2] It has some sequence similarities with UPOV and ABV.[15]

UPOV was first isolated on Upolu Cay in the Great Barrier Reef, Australia in 1966, from soft-bodied ticks of the species Ornithodoros capensis associated with the sooty tern (Onychoprion fuscatus). No natural vertebrate host has been identified, but the virus is highly pathogenic to mice in laboratory infections. The virion can either be spherical, with a diameter in the range 75–95 nm, or slightly ovoid, with a range of dimensions from 75 nm × 85 nm to 105 nm × 120 nm. The genome has six RNA segments. It is most similar to ABV, with some similarity to THOV and JOSV.[15]

DHOV was first isolated from Hyalomma dromedarii hard-bodied ticks infesting camels in Gujarat, India, in 1961.[6] It has since been observed in eastern Russia, Pakistan, Egypt, Saudi Arabia, Kenya and southern Portugal. The vector is usually a species of Hyalomma, such as H. marginatum.[6][13][31][46][47]

Where DHOV is prevalent, antibodies to the virus have been documented in camels, goats, horses, cattle and humans.[6][13] The virus has been isolated from a wild hare, Lepus europaeus.[31][48] DHOV can infect humans by the aerosol route after accidental laboratory exposure, causing a febrile illness and encephalitis.[6][8][31] Under laboratory conditions it is highly pathogenic for mice, and has been proposed as a model system for highly pathogenic influenza.[6] It has also been shown to infect birds, with the virus being isolated from a cormorant,[49] and antibodies being observed in waterfowl.[13][15]

DHOV has seven RNA segments.[13]

Electron micrograph of a filamentous form of Bourbon virus (scale bar: 100 nm)

Batken virus was first isolated from hard-bodied ticks of the species Hyalomma plumbeum plumbeum infesting sheep near the town of Batken, Kirghizia, now in Kyrgyzstan, in 1970.[9][30] It has also been found to infect mosquitoes of the species Aedes caspius Pallas and Culex hortensis Ficalbi, also in Kyrgyzstan.[50] Its geographical range is limited to Central Asia, Transcaucasia and the area to the north of the Caspian Sea.[50] In the laboratory it is highly pathogenic for mice, hamsters and chickens.[30] The virion is variable in shape, with spherical and filamentous forms being observed; it has a diameter of 50–100 nm.[9] Batken is considered a DHOV subtype; the viruses have a high degree of sequence identity (90% in the envelope glycoprotein; 96–98% in other proteins), and their antibodies crossreact.[13][50]

Bourbon virus was identified in 2014 by next-generation sequencing of a blood sample from a man from Bourbon County, Kansas, USA, who became ill a few days after being bitten by multiple ticks, and subsequently died. It is the only known thogotovirus to be associated with human disease in the Western hemisphere. As of February 2015, Bourbon virus has not been isolated from ticks, insects or non-human vertebrates. The virus is variable in shape, with filamentous as well as spherical forms; it has a diameter broadly in the range 100–130 nm. The genome contains at least six RNA segments. It is most similar to DHOV and Batken virus.[7]

Oz virus was first characterised in 2018 after isolation from the hard tick Amblyomma testudinarium in Ehime, Japan. [DOI: 10.1016/j.virusres.2018.03.004]. The first human case, a 70 year old female patient who died of myocarditis with isolation of Oz virus on autopsy, was reported on 23.6.2023 by the Japanese Ministry of Heath.