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

T淋巴细胞对绵羊临床疾病、免疫反应和蓝舌病毒传播的影响

基本信息

批准号：
BB/P006841/1
负责人：
Karin Darpel
金额：
$ 37.81万
依托单位：
The Pirbright Institute
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FP006841%2F1
关键词：
Impact lymphocytes clinical disease immune

项目摘要

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.

由库蚊叮咬蚊子传播的病毒会在世界各地的反刍动物中引起重要的经济疾病。目前，其中最重要的是蓝舌病毒(BTV)，在过去十年中，仅在西北欧就造成了超过1亿欧元的损失。该病毒对英国反刍动物生产构成持续威胁，突出表现为2015年法国再次出现8型血清菌株。感染BTV通常会导致绵羊的严重疾病，尽管牛的临床疾病较轻，但对生产参数的不利影响会对经济造成损害。康复的受感染动物被保护免受BTV再次感染，但只能由相同血清型的菌株保护。同样，商业疫苗也是可用的，但只能预防相同血清型的再次感染。到目前为止，至少已检测到27种BTV血清型，这些血清型的全球分布不断变化。尽管2008年疫苗接种成功地根除了来自英国和北欧的BTV-8毒株，但BTV的多血清型特性给病毒的控制带来了一个主要问题。设计针对多种BTV血清型提供交叉保护的新疫苗需要详细了解导致病毒从受感染动物身上清除的免疫反应机制。然而，我们对这些抗BTV免疫反应的了解仍然很肤浅。在这个项目中，我们将探索一种关键细胞类型(T淋巴细胞，也称为T细胞)在抗病毒免疫反应中的核心作用，无论是通过使其他细胞产生抗病毒抗体，还是通过直接清除受病毒感染的细胞。T细胞存在于不同的亚群中，但到目前为止，T细胞亚群在免疫反应中对BTV的具体贡献尚不清楚。此外，已知T细胞亚群本身也会感染BTV。然而，目前还不清楚这些T细胞亚群的感染在多大程度上导致了在BTV感染动物中检测到的大量病毒。我们已经发现的一个关键的观察结果是，库蚊的吸血导致大量的T细胞(以及其他细胞)聚集到咬伤部位。因此，T细胞也有可能影响病毒从昆虫媒介传播到昆虫媒介。在可控的实验条件下，现实地检验自然哺乳动物宿主、昆虫媒介和病毒之间的复杂相互作用是具有挑战性的，大多数实验研究要么通过针头接种病毒进入宿主，要么使用模式宿主物种，如啮齿动物。在这个项目中，我们将研究T细胞在绵羊体内的作用，绵羊是BTV的自然宿主，并利用受感染的叮咬蚊进行BTV的传播。通过给绵羊接种抗体来去除特定的T细胞亚群，我们可以进行研究，揭示每个亚群在对BTV的免疫反应中的重要性。我们将探索的关键领域包括是否产生更多或更少的BTV，以及临床疾病是否因缺乏特定的T细胞亚群而不同。我们还将测量抗BTV抗体和抗病毒细胞因子的产生，以及剩余T细胞识别BTV成分的可能性。此外，未受感染的库蚊将被允许以感染BTV的绵羊为食，以便对病毒传播进行检测。这项全面的BTV绵羊感染研究将提供关于T细胞亚群在BTV产生、抗BTV免疫反应、临床后果和病毒传播方面的特定作用的迫切需要的数据。虽然所获得的结果对推进BTV的治疗和控制将特别重要，但我们使用自然传播系统可能会增强对这一过程的理解，这与其他虫媒病毒有关。