Thogotovirus is a genus of viral envelope 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 – viruses that are transmitted by , in this case usually . Thogotoviruses can replicate in both tick cells and vertebrate cells; one subtype has also been isolated from . A consequence of being transmitted by blood-sucking vectors is that the virus must spread systemically in the vertebrate host – unlike , which are transmitted by respiratory droplets and are usually confined to the respiratory system.
The genus contains eight species. A wide range of are infected by members of the genus; some types also infect . THOV causes disease in livestock. THOV, DHOV and Bourbon virus can infect humans, and have occasionally been associated with human disease.
History
Thogoto virus (THOV) and
Dhori virus (DHOV) were identified in the early 1960s in
Kenya and
India, respectively.
Two cases of human disease associated with THOV occurred in 1966, and a Russian laboratory accident in the 1980s showed that DHOV can also cause disease in humans.
The two viruses were originally considered to be
Bunyaviridae, but characterisation in the 1980s and early 1990s revealed similarities with
.
A genus of "Thogoto-like viruses" within
Orthomyxoviridae was proposed in 1995, and recognised by the ICTV under the name
Thogotovirus the following year.
The name comes from
Thogoto Forest in Kenya, where THOV was first discovered.
Since then, sequence analysis of five viruses discovered in the 1960–70s but unclassified or tentatively assigned to
Bunyaviridae led to their being proposed as additional members of the genus.
A further proposed member of the genus was characterised by next-generation sequencing in 2014.
Virology
The virus particle is
viral envelope. It is generally spherical or
ovoid, with a diameter in the range 80–120 nm.
Some filamentous forms are observed in THOV, Batken and
.
The
single-stranded, –
RNA genome is linear and segmented, with six or seven segments of 0.9–2.3 kb and a total size of around 10 kb.
of segments between strains has been observed in both ticks and mammals experimentally infected with more than one thogotovirus, but its significance in natural infections is unknown.
Viral proteins
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.
The thogotovirus glycoprotein is not similar to the influenza virus glycoproteins (haemagglutinin and neuraminidase), and instead shows some similarities with the gp64 glycoprotein of , which infect insects.
THOV and JOSV
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 RNA splicing to encode the matrix protein or unspliced to encode ML, which has 38 additional at its C-terminus.
Life cycle
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.
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.
In one study, this inhibitory effect was shown to be caused by MxA preventing the transport of the THOV genome into the nucleus.
As orthomyxoviruses do not encode a capping enzyme, initiation of transcription involves the virus cutting the five-prime 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.
The virus assembles by the cell membrane and leaves the cell by budding.
Epidemiology
Most thogotoviruses have been shown to infect arthropods, generally
Ixodidae or
Argasidae , which are
,
but in one case
, which are
.
Members also infect
and a wide range of wild and domestic
, including
,
,
,
,
,
,
,
sheep and
cattle.
Three types –
Thogoto virus,
Dhori virus and
Bourbon virus – have been shown to infect humans.
They have a wide geographical range.
Transmission to vertebrates usually occurs via a tick vector. THOV persists in the tick, remaining in the organism as it goes through its developmental stages; this is called transstadial transmission.
Host interaction and disease
Ticks
No major pathological changes are observed in
Rhipicephalus ticks infected with THOV.
The virus is concentrated in the
synganglion (the tick
brain) early on in the
hematophagy process, with the proportion of virus located in the
increasing during the late phase of blood-feeding.
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.
Vertebrates
In the laboratory setting, several members of the genus cause severe disease in
mouse and
.
Systemic spread of the virus occurs, with pathological effects present in multiple organs and systems, including the
brain,
liver,
lymphatic system, and sometimes the
and
small intestine.
are a major target cell for DHOV.
DHOV infection in mice resembles experimental influenza infection in mice and
as well as fatal H5N1 influenza infection of humans, and has been proposed as a model for this disease.
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.
Treatment and prevention
No specific treatment or
vaccine is available for thogotoviruses, as of February 2015. The
antiviral drug ribavirin, which has a broad spectrum of activity that includes some other orthomyxoviruses,
has been shown to inhibit DHOV replication
in vitro in a single study.
Supportive therapy is used for THOV disease,
and has been recommended by the US Centers for Disease Control and Prevention for infection with Bourbon virus. As with other
, avoidance of contact with the vector is central to prevention.
Species and strains
The genus contains the following species, listed by scientific name and followed by the exemplar virus of the species:
|
|
| Araguari | 6 | 105 | Unknown | Gray four-eyed opossum, mouse | S. America |
| Aransas Bay | 6 | 75–140 | Ornithodoros ticks | Mouse | N. America |
| Batken | | 50–100 | Hyalomma ticks, Aedes and Culex mosquitoes | Chicken, hamster, mouse | Asia |
| Bourbon virus | ≥6 | ~100–130 | Amblyomma ticks | Human | N. America |
| Dhori virus | 7 | | Hyalomma ticks | , hare, horse, human, mouse, | Africa, Asia, Europe |
| Jos | ≥6 | 85–120 | Amblyomma and Rhipicephalus ticks | Mouse, zebu | Africa |
| Thogoto | 6 | 100 | Amblyomma, Hyalomma and Rhipicephalus ticks | Banded mongoose, donkey, human, , | Africa, Asia, Europe |
| Upolu | 6 | 75–120 | Ornithodoros ticks | Mouse | Australia |
|
THOV-like viruses
Thogoto virus (THOV)
Thogoto virus was first isolated from ticks gathered from cattle in the
Thogoto Forest region of
Kenya, near
Nairobi, in 1960,
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.
Despite this wide geographical range, the virus shows only limited variation.
Its vectors include various hard-bodied ticks, including
Amblyomma,
Hyalomma and
Rhipicephalus species.
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).
The virus particle is generally spherical with some filamentous forms; the diameter is around 100 nm.
Araguari virus
The Araguari virus was first isolated from a Gray four-eyed opossum (
Philander opossum) in Serra do Navio, Amapá,
Brazil in 1969.
Its method of transmission is unknown.
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.
Aransas Bay virus (ABV)
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.
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.
Jos virus (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.
It has some sequence similarities with UPOV and ABV.
Upolu virus (UPOV)
UPOV was first isolated on
Upolu Cay in the Great Barrier Reef,
Australia in 1966, from soft-bodied ticks of the species
Ornithodoros 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.
DHOV-like viruses
Dhori virus (DHOV)
Dhori virus was first isolated from
Hyalomma hard-bodied ticks infesting
in
Gujarat,
India, in 1961.
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.
Where DHOV is prevalent, antibodies to the virus have been documented in camels, goats, horses, cattle and humans.
DHOV has seven RNA segments.
Batken virus
Batken virus was first isolated from hard-bodied ticks of the species
Hyalomma infesting sheep near the town of
Batken,
Kirghizia, now in
Kyrgyzstan, in 1970.
It has also been found to infect
of the species
Aedes and
Culex, also in Kyrgyzstan.
Its geographical range is limited to Central Asia,
Transcaucasia and the area to the north of the
Caspian Sea.
In the laboratory it is highly pathogenic for mice, hamsters and chickens.
The virion is variable in shape, with spherical and filamentous forms being observed; it has a diameter of 50–100 nm.
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.
Bourbon virus
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.
Oz virus
Oz virus was first characterised in 2018 after isolation from the hard tick Amblyomma testudinarium in Ehime, Japan. DOI:. 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.
Notes and references
External links
