Orbiviruses and Bluetongue Virus

Abstract

Bluetongue virus (BTV) is the type species of the genus Orbivirus within the family Reoviridae (the largest double‐stranded ribonucleic acid (dsRNA) virus family). BTV is an arthropod‐borne pathogen that is transmitted by the bites of its vector, the Culicoides biting midges, which transmit the virus between its ruminant hosts. The virus can infect most species of domestic and wild ruminants. BT clinical signs are most common in sheep and some species of deer. In recent years, the distribution of BTV has changed considerably, particularly in Europe. New outbreaks have occurred each year from 1998 in southern and central Europe, involving several strains from 10 different serotypes. In 2006, BTV serotype 8 caused an outbreak approximately 5° further north in Europe than ever before, infecting ruminants in a wide area across northern Europe. A new virus (Toggenburg virus) has been identified in goats from Switzerland in 2008 and designated as the twenty‐fifth serotype of BTV and another one isolated from goats in Corsica in France more recently and was designated as serotype 27. Additional serotypes have been detected/isolated, bringing now the number of serotypes to 29.

Key Concepts

  • Genus Orbivirus is the most diverse genus of family Reoviridae containing 32 virus species.
  • Bluetongue disease affects mainly sheep causing severe clinical signs and high mortality.
  • Bluetongue virus is transmitted by competent species of Culicoides midges.
  • Phylogenetic analysis identifies two major groups of orbiviruses, those with their subcore shell protein (T2 protein) being the VP2 and those with the T2 being VP3. Orbiviruses are nonturreted members of family Reoviridae, and the atomic structure of BTV core has been determined.

Keywords: orbivirus; Reoviridae; dsRNA virus; BTV; bluetongue; Culicoides

Figure 1. Phylogenetic trees for (a) the ‘variable’ orbivirus outer capsid protein VP2 and (b) the ‘conserved’ orbivirus subcore shell protein (T2). (a) VP2 is the most variable outer capsid protein and is the major serotype‐specific and neutralisation antigen. (b) The T2 protein is the VP3 for the Culicoides‐borne orbiviruses and the VP2 in mosquito‐borne and tick‐borne orbiviruses (the phylogenetic tree is based on the sequences encompassing amino acids 393 to 548 relative to BTV‐10 sequence). BTV, Bluetongue virus; AHSV, African horsesickness virus, CHUV, Chuzan virus; PHSV, Peruvian horsesickness virus; ELSV, Elsey virus; YUOV, Yunnan orbivirus (P, Peru; Aus, Australia; Ch, China); BRDV, Broadhaven virus; DAGV, Daguillar virus; PRV, Paroo River virus; PIAV, Picola virus.
Figure 2. Unrooted neighbour‐joining (NJ) tree showing the relationships between deduced amino acid sequences of VP2/Seg‐2 from the 24 BTV serotypes. This NJ tree was constructed using MEGA programme version 5 using the p‐distance algorithm and the full‐length VP2 sequences of BTV types 1 to 27. The different serotypes are distinct but show some relationships (grey bubbles) that mirror the serological relatedness (cross‐reactions) that are known to exist between different serotypes. These groupings are reflected in the nucleotide sequences of genome segment 2 and the 11 distinct groups identified as nucleotypes A–K.
Figure 3. Diagram of the replication cycle of Bluetongue virus (BTV). BTV particles bind to cell surface receptors and are transported, via clathrin‐coated pits, to endosomes. The outer capsid layer of BTV is pH sensitive and may be modified, or lost, as the contents of the endosome become more acidic. An unknown mechanism, possibly triggered by the low pH, allows the virus core to leave the early endosome, crossing the endosomal membrane and entering the cytoplasm. Once in the cytoplasm, the core synthesises mRNA copies (shown in blue) of the viral genome segments. These act as templates for the synthesis of viral proteins (shown in green) by the host cell ribosomes. The mRNAs also associate with newly synthesised viral proteins to form nascent progeny core particles. The assembly process and negative‐strand RNA synthesis within the nascent particles, to reform the dsRNA genome segments, take place within the viral inclusion bodies (shown in red). These are seen by electron microscopy as granular matrices that are initially associated with the infecting parental core. As the progeny virus cores leave the viral inclusion body, outer capsid proteins are added to form mature virus particles, which can leave the cell by budding, extrusion or cell lysis. Released particles can reinfect the same or other cells, helping to spread the infection and increasing the chances of genome segment reassortment. The nucleus is not shown in this diagram and is not believed to play any significant role in the processes of BTV replication.
Figure 4. Electron micrographs of (a) Bluetongue virus 1 (South Africa) virus particles; (b) infectious subviral particles and (c) core particles. Particles were purified and stained with 2% methylamine tungstate.
Figure 5. Bluetongue virus (BTV) structure. (a) Model of the outer capsid layer of BTV particles, from cryoelectron microscopy. Courtesy of Hewat et al., 1992 with permission. Structures thought to represent VP2 shown in blue and VP5 shown in yellow. Models from X‐ray crystallography of the native core particle. The outer core surface (b), composed of 260 trimers of VP7(T13), arranged with T = 13 symmetry. The chemically identical but structurally different trimers are coloured and named in order of increasing distance from the fivefold axes of symmetry (P, red; Q, orange; R, yellow; S, green and T, blue; situated at the threefold axes). (c) The BTV‐1 subcore shell is composed of 120 copies of VP3(T2), arranged with T = 2 symmetry. The chemically identical but structurally different ‘A’ (green) and ‘B’ (red) molecules are shown. (d) The dsRNA genome can be modelled as concentric shells of RNA, with helices in the outermost shell spiraling around and away from the position of TCs, that are situated in holes in the RNA layers, at the fivefold axes of the icosahedral particle. Courtesy of DI Stuart, J Grimes, P Gouet, J Diprose, R Malby and PPC Mertens.
Figure 6. Cross‐sectional diagram of the Bluetongue virus particle.
Figure 7. The atomic structure of the BTV capping enzyme VP4(CaP) coloured by domain. From the N‐ to the C‐terminus: the kinase‐like (KL, in blue) domain, which is thought to interact with the polymerase; the N7‐methyltransferase (N7MT, in green); the O2‐methyltransferase (O2MT, in red) and the guanylyltransferase (GTase, in yellow).
Figure 8. The atomic structure of the BTV NS2 N‐terminal domain. The structure is composed predominantly of two β sheets arranged as a sandwich (dimer). The putative RNA‐binding domain is towards the bottom of the molecule (circled with dashed red line).
Figure 9. A sheep infected by Bluetongue virus serotype 4. Excess salivation and associated respiratory distress observed in a sheep at 6 days postinfection with BTV. Courtesy of DI Stuart, J Grimes, P Gouet, J Diprose, R Malby and PPC Mertens.
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Further Reading

Hill CL, Booth TF, Prasad BVV, et al. (1999) The structure of a cypovirus and the functional organisation of dsRNA viruses. Nature Structural Biology 6: 565–568.

Mellor PS, Baylis M, Hamblin C, Calisher CH and Mertens PPC (1998) African horse sickness. Archives of Virology, Supplement 14: 1–342.

Mertens PPC (1999) Orbiviruses and coltiviruses: general features. In: Webster RG and Granoff A (eds) Encyclopedia of Virology, 2nd edn, pp. 1043–1061. London: Academic Press.

Roy P (1989a) Bluetongue virus genetics and genome structure. Virus Research 13: 179–206.

Roy P (1989b) Bluetongue virus proteins. Journal of General Virology 73: 3051–3064.

Roy P and Gorman BM (1990) Bluetongue viruses. Current Topics in Microbiology and Immunology 162: 1–200.

Roy P and Mertens PPC (1999) Orbiviruses and coltiviruses: molecular biology. In: Webster RG and Granoff A (eds) Encyclopedia of Virology, 2nd edn, pp. 1062–1074. London: Academic Press.

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Mertens, Peter, Mohd Jaafar, Fauziah, and Attoui, Houssam(Jun 2015) Orbiviruses and Bluetongue Virus. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001010.pub3]