Molecular and reverse genetics studies of orbivirus transmission host responses epidemiology and diagnostic systems

Lead Research Organisation: The Pirbright Institute
Department Name: UNLISTED

Abstract

Since 1998, there have been multiple incursions of bluetongue into Southern, Central and Northern Europe. These outbreaks have involved at least 12 distinct bluetongue virus (BTV) strains, belonging to 9 different serotypes and have lead to the death of more than two million animals. In addition, significant economic losses have been incurred due to loss in productivity, restrictions in animal movements and trade as part of control programmes. These events demonstrate that the entire European Union is now at risk from further introductions of BTV, and potentially of other BTV-related related Orbiviruses, particularly those also transmitted by Culicoides vectors (including African horse sickness virus [AHSV], epizootic haemorrhagic disease virus [EHDV] and equine encephalosis virus [EEV]). Worryingly, AHSV, EHDV and EEV have been detected just outside the EU in Israel, Turkey, as well as North and West Africa and now pose a further significant threat to livestock in Europe. This proposal will establish 'OrbiNet', a network of 9 laboratories focussing on research on BTV and related orbiviruses in 8 European countries and Israel. The 'OrbiNet' Partners include university departments, government laboratories and reference centres that already work on orbiviruses and associated diseases. The goals of OrbiNet are to provide training, share reagents and expertise, and conduct targeted research programmes with the overall aim to better understand orbivirus transmission, epidemiology, pathogenesis and develop better diagnostic techniques. These activities will enhance research capacity and capability and increase the knowledge base and expertise within partner laboratories, thus underpinning the development of improved tools / strategies to prevent and control these economically important animal pathogens. OrbiNet will closely liaise with the scientific community, government agencies, the EU and industry in order to exploit the knowledge generated and help to inform animal health research policies and activities at the EU level.

Technical Summary

'OrbiNet' will build a network of research laboratories across 8 European countries and Israel, focussing on bluetongue and other important diseases (including epizootic haemorhagic disease and African horse sickness) that are caused by closely related orbiviruses. The Partners include university departments, government laboratories and reference laboratories that are already established as research centres for these important and emerging pathogens. The OrbiNet coordinator, Prof. Peter Mertens, (IAH Pirbright) has 29 years BTV research experience, and is well suited to steer the network. The Principal Investigators have established and complementary expertise in molecular virology, pathogenesis, epidemiology, viral diagnostics, virus structure, vaccinology and immunology, with access to appropriate resources, facilities and reagents to meet project goals. WP leaders will meet every 6 months to monitor progress and help co-ordinate specific aspects of the programme. Exchange visits between participating laboratories, training modules, and joint meetings / publications will help disseminate results of the work carried out and cement long term relationships.

Planned Impact

The spread of BTV has had a major impact on sustainability and productivity of livestock industries across Europe. It has restricted and damaged trade between European Member States, caused animal health problems and major economic losses associated with fatalities, reduced productivity and associated surveillance control programmes. BTV has been introduced on multiple occasions (since 1998) to both Southern and Northern Europe, resulting in disease outbreaks, which pose a continuing risk to the region and indicating an increased risk posed by related orbiviral diseases transmitted by the same insect vectors. The importance of research in these areas is highlighted by the success of molecular epidemiology studies and the development of novel diagnostic assay systems, that have been developed by members of the OrbiNet partnership, as well as the European vaccination programmes (particularly against BTV-1 and 8). However, it is clear that there is still a need for further improvement in diagnostic systems, as well as a better understanding of the molecular mechanisms and genetic determinants of the host's immune response to the virus, determinants of virus transmission by the insect vector, overwintering (e.g. by vertical transmission), pathogenesis and virulence. Further detailed information in these areas will help us assess risks and develop better control strategies for bluetongue and related diseases. The work of the project will involve multiple partner laboratories across Europe (through the OrbiNet consortium), which will be funded via their own national authorities. OrbiNet will build capacity and capability in many areas of orbivirus research, in a manner that is particularly relevant to these economically important transboundary diseases. Each of the participating laboratories will have the opportunity to gain new skills in reverse genetics technologies for this important group of viruses, which will open up significant future research opportunities. Exchange visits by staff and students, as well as joint meetings, will help to disseminate information and technologies. The research outputs of the UK partners (and the consortium as a whole) will be of importance to policy makers and the livestock-farming community, as well as potentially to vaccine maufacturers, diagnostic laboratories and manufacturers of diagnostic assay systems.

Publications

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Arenas-Montes AJ (2013) Serosurveillance of orbiviruses in wild cervids from Spain. in The Veterinary record

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Belaganahalli MN (2015) Genetic characterization of the tick-borne orbiviruses. in Viruses

 
Description Reverse genetics (RG) technology for bluetongue virus (BTV) was successfully established in several partner laboratories, both in the UK and in other European countries.
These technologies have been used at TPI, to explore the genetic basis for the restriction of bluetongue virus type 26 infection and transmission by adult Culicoides. It was shown that four of the viral genome segments/proteins, restrict its infection or replication in insect-vector cells but not in mammalian cells .
The RG technology has also been used to explore any restrictions on the process of genome segment exchange (reassortment) between different BTV isolates. It was concluded that each genome segment can be freely exchanged between different virus lineages or genotypes.
The creation of an engineered BTV strain expressing a flourescent protein, was used to explore infection and replication of BTV in drosophila (in collaboration with the University of Glasgow) and forms the basis of a current collaborative Ph.D. project to explore BTV replication and transmission in adult Culicoides vector insects.
Exploitation Route The reverse genetics technologies established for BTV are being extended to other orbiviruses including African horse sickness virus (AHSV).

These technologies have been used by partners in the original ObiNet consotium to develop novel vaccine components/ strategies for BTV. These include a set of synthetic vaccine strains for the generation of inactivated vaccines against each BTV serotype (university of Glasgow). Disabled vaccine strains that can be used safely to vaccinate individual animals removing any risk of onward transmission and reducing the risk of reassortment with field strains were also developed by a partner in the Netherlands.

The identification of BTV genes that can restrict replication of the virus (BTV-26) in insect vectors suggests that there may be a genetic basis for the apparent restriction of certain BTV strains or serotypes to certain geographic regions (e.g. north and south Europe) , that could be based on the distribution of different insect vector species or populations.
Sectors Agriculture, Food and Drink

 
Description The reverse genetics sequencing and molecular technologies that were disseminated through this project have been used by project partners to develop novel vaccine components and strategies for bluetongue virus. The full utilisation of these novel materials will depend on vaccine trials and licensing, which can be lengthy processes in their own right.
Sector Agriculture, Food and Drink
Impact Types Economic

 
Description "Understanding pathogen, livestock, environment interactions involving bluetongue virus" (PALE-Blu)
Amount € 6,300,000 (EUR)
Funding ID 727393-2 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 06/2016 
End 11/2020