Impact of T lymphocytes on clinical disease, immune responses and transmission of bluetongue virus in sheep

点击翻译按钮获取中文摘要

Viruses transmitted by Culicoides biting midges cause economically important diseases in ruminants worldwide. Currently, the most important of these is bluetongue virus (BTV), which has inflicted over 1000m Euros of damage in North-West Europe alone during the past decade. This virus represents an ongoing threat to UK ruminant production, highlighted by re-emergence of a serotype 8 strain in France during 2015. Infection with BTV often causes severe disease in sheep and although clinical disease is milder in cattle, adverse effects on production parameters are economically damaging. Infected animals which recover are protected from BTV re-infection, but only by strains of the same serotype. Similarly, commercial vaccines are available but only protect against re-infection by the same serotype. To date, at least 27 serotypes of BTV have been detected and the global distribution of these constantly changes. Although vaccination successfully led to the eradication of a virulent BTV-8 strain from the UK and Northern Europe in 2008, the multiple serotype nature of BTV presents a major problem to control of the virus.Designing new vaccines that provide cross-protection against multiple BTV serotypes requires a detailed understanding of the immune response mechanisms that result in virus clearance from infected animals. However, our knowledge of these anti-BTV immune responses remains superficial. In this project we will explore the role of a key cell type (T lymphocytes also called T cells) that is central to the anti-viral immune response, either by enabling other cells to produce anti-viral antibodies, or by directly eliminating virus infected cells. T cells occur in different subsets, but so far the specific contribution of subsets in the immune response to BTV is unknown. Additionally, it is known that T cell subsets can become infected with BTV themselves. However , it is unclear how much infection of these T cell subsets contributes to the high amounts of virus detected in BTV infected animals. A key observation we have shown is that blood-feeding of Culicoides leads to the recruitment of high numbers of T cells (among other cells) to the biting sites. Hence, T cells also have the potential to influence virus transmission from and to the insect vector. It is challenging to realistically examine complex interactions between natural mammalian hosts, insect vectors and viruses under controlled experimental conditions and most experimental studies are compromised by either needle-inoculating the virus into the host and/or the use of model host species such as rodents. In this project we will study the role of T cells directly in sheep, a natural host for BTV and carry out transmission of BTV using infected biting midges. By inoculating sheep with antibodies to remove specific T cell subsets we can conduct studies revealing the importance of each subset in the immune response to BTV. Key areas we will explore include whether more or less BTV is produced and whether clinical disease differs according to the absence of a specific T cell subset. We will also measure the production of anti-BTV antibodies and anti-viral cytokines, alongside the potential for the remaining T cells to recognise BTV components. In addition, uninfected Culicoides will be allowed to blood-feed on BTV infected sheep enabling virus transmission to be examined. Cell populations and skin inflammation in response to blood-feeding of these biting midges will also be compared between treatment and control groups.This comprehensive BTV sheep infection study will provide much needed data on the specific role of T cell subsets on BTV production, anti-BTV immune responses, clinical consequences and virus transmission. While the results obtained will be particularly important to advance BTV treatment and control, our use of a natural system of transmission is likely to yield an enhanced understanding of this process that is relevant to other arboviruses.