Role of T cells in recovery from bluetongue virus infection in calves

Lead Research Organisation: The Pirbright Institute
Department Name: UNLISTED

Abstract

Bluetongue (BT) is an economically important infectious disease of sheep, cattle, goats and deer caused by bluetongue virus (BTV), which is spread by types of biting midges. Animals infected with BTV develop fever, reddening and swelling of the lips, mouth, nasal passages and eyelids, lose condition rapidly, develop muscle degeneration and lameness and may die from the disease. There are at least 24 different types of BTV and, until recently, the disease was largely confined to regions within Africa, Asia, the Americas and Australia. However, as a result of climate change and warmer weather in Europe, BTV-infected midges spread into southern Europe and in 2006 an outbreak of bluetongue occurred in some northern European countries. This was the first time that BTV has been known in northern Europe and in August 2007, the virus spread to the UK. During late 2007/early 2008 BTV serotype 1 arrived in southern France and its distribution overlaps with BTV-8. This raises the possibility that these strains of virus will exchange genes. This may enhance the ability of BTV-1 mixed progeny strains to spread northwards and increase the threat of a second serotype (BTV-1) in northern Europe and the UK. During 2008, a third strain of virus, BTV-6, was detected in the Netherlands and Germany. Control measures in recently infected countries include restrictions on animal movement, which have a significant economic impact, and vaccination. The aims of BTV vaccination are to prevent clinical disease; prevent new animals becoming infected and to allow the safe movement of animals from infected areas. Voluntary vaccination with an inactivated BTV-8 vaccine was introduced into the UK in 2008. Both disabled (modified live) and killed BTV vaccines have been used, but they both have a number of shortcomings. The main problem is that immunity induced by one serotype of BTV only protects against infection with the same serotype. Modified live virus vaccines, which are cheap to produce and generate protective immunity after a single dose, can induce clinical disease in certain susceptible breeds of sheep and have the potential to be spread by midges with the possibility of changing back to a virus that can cause severe disease. Although killed vaccines are safe if properly produced, it is difficult to determine whether animals have been infected or vaccinated; production costs are high and there are marked differences in the response of different breeds of animals to vaccination. Since the current inactivated BTV-8 vaccines are entirely BTV serotype specific, a new vaccine would need to be developed to protect against the potential threat to the UK of BTV-1 and BTV-6, increasing the cost of laboratory diagnosis and distribution of the vaccines. Induction of immune responses that protect against a number of different BTV serotypes could play a significant part in the development of a more widely cross-protective BTV vaccine. Whereas antibody to BTV tends to be serotype-specific, there is evidence that cell-mediated immunity (T cells) is more cross-reactive. However, the role of T cells in protection against BTV is not clear. In this project, we will investigate the role of cell-mediated immunity in recovery from BTV infection in cattle. The findings from these studies will identify elements of the immune response that are responsible for protection and this information will facilitate the development of novel BT vaccine strategies.

Technical Summary

Bluetongue virus (BTV) causes a non-contagious, infectious, arthropod-borne acute haemorrhagic fever of domesticated and wild ruminants. There are at least 24 serotypes of BTV, and neutralising antibodies, which can mediate protection, are largely serotype-specific. As a result of climate change, BTV appeared in northern Europe for the first time during 2006, with devastating effects on the sheep and cattle industry. The virus, BTV-8, spread to the UK in 2007, and in 2008, BTV-1 appeared in southern France and BTV-6 in the Netherlands and Germany, representing an additional threat to the UK. Vaccination plays an important part in the control of BT. However, current inactivated BTV vaccines are relatively crude and are serotype-specific. New and improved vaccines need to be developed to control the threat posed by BTV-8 and incursions by other serotypes. The development of a vaccine that induces a cross-serotype immune response could play a significant part in development of more effective vaccination strategies. There is evidence that some T-cell responses are cross-reactive and play a role in protection in sheep. However, the T cell subsets that mediate protection are not clearly understood. The aim of this project is to determine the role of different T-cell subsets in the resolution of BTV infection in cattle. This will be achieved by depleting cattle of individual T-cell subsets using monoclonal antibodies. This project will identify components of the T-cell response that are important in controlling BTV and will provide the basis for future studies to determine the cross-reactivity and antigenic specificity of the protective T cells. This informaiton will aid the development of novel more widely cross-reactive, BT vaccine strategies.

Publications

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Description A role for CD4 T cells in controlling bluetongue virus (BTV) replication was identified. Replication-defective adenovirus vaccine vectors expressing the non-structural genes of BTV were constructed and were used to immunise mice to produce monoclonal antibodies and to evaluate their ability to induce cross-protective immunity to different BTV serotypes.
Exploitation Route The development of monoclonal antibodies to the BTV non-structural (NS) proteins will aid studies on host-pathogen interactions. If adenovirus-vectored vaccines expressing the NS proteins of BTV are found to induce cross-protection immunity in a mouse model of BTV infection, further studies will be undertaken to evaluate their efficacy in goats, sheep, & cattle, the main targets of BT. Such a cross-protective vaccine would have commercial interest. The findings from the study led to a further successful grant application to study the role of T-cell in BTV infection in sheep. In addition, the AdV vectors expressing NS genes were used by others to determine their ability to induce protective immunity in a mouse model of BTV infection.
Sectors Agriculture, Food and Drink

 
Description Animal Sciences Committee
Amount £360,000 (GBP)
Funding ID BB/P006841/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2017 
End 03/2019
 
Title Replication-defective adenovirus vectors expressing BTV NS proteins 
Description AdV expressing Bbluetongue virus non-structural proteins are being used to produce monoclonal antibodies and as a vaccine candidate to induce cross-protection against different serotypes of BTV 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact None yet 
 
Description Protective efficacy of adenovirus-vectored bluetongue virus non-structural proteins 
Organisation French National Institute of Agricultural Research
Department INRA Versailles
Country France 
Sector Public 
PI Contribution Production of adenovirus vectored bluetongue virus non-structural proteins NS1, NS2 & NS3
Collaborator Contribution Evaluation of the immunogenicity and protective efficacy of AdV-vectored BTV NS in a mouse model of BTV
Impact AdV immunised mice were protected against BTV infection
Start Year 2015
 
Description Surrey University seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Karin Darpel was an invited speaker to the University of Surrey Faculty of Health and Medical science seminar (equivalent to our external seminar) & talked about 'Bluetongue virus - why an insect-borne virus has remained a threat to ruminants in Europe'
Year(s) Of Engagement Activity 2016