Thogotovirus is a genus of enveloped RNA viruses 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. The genus contains eight species. A wide range of mammals are infected by members of the genus; some types also infect birds. 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 bunyaviruses, but characterisation in the 1980s and early 1990s revealed similarities with influenza viruses. 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 enveloped. It is generally spherical or ovoid, with a diameter in the range 80–120 nm. Some filamentous forms are observed in THOV, Batken and Bourbon viruses. 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. Reassortment 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 baculoviruses, which infect insects. It also has some similarity with the haemagglutinin of Quaranfil virus of the related genus of tick-transmitted orthomyxoviruses Quaranjavirus. 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. This apparent receptor specificity for arthropod cells does not prevent most thogotoviruses from infecting vertebrates. 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). THOV and JOSV 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). 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. No product has yet been identified for the seventh segment, observed in DHOV.
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 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. 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.
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