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Development of multi-parametric measurements of the circulating immune response to Feline Tuberculosis to improve the understanding and diagnosis of t

开发对猫结核病循环免疫反应的多参数测量，以提高对猫结核病的理解和诊断

基本信息

批准号：
1997899
负责人：
金额：
--
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Studentship
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=studentship-1997899
关键词：
Development multi parametric measurements circulating

项目摘要

Tuberculosis (Tb) is a major global concern in humans and animals. In the UK, Tb is an increasing problem in cattle, badger and other domestic and wildlife species, including pet cats. We have shown that cats in the UK are significantly at risk of Tb, as ~1% of all routine feline tissue biopsies have histopathological changes consistent with mycobacteriosis (Gunn-Moore et al. 2013); at least 15% of these are due to M. bovis, and 19% M. microti (the vole/rodent bacillus) (Gunn-Moore et al. 2011). Some M. bovis infections in cats progress extremely rapidly, with large numbers of organisms present within the affected tissues and exudates; this poses a major concern given the recently recognised cat to human zoonotic risk (Roberts et al. 2014). We hypothesise that the outcome of exposure of domestic cats to M. bovis or M. microti, and the likelihood of zoonotic transmission, is determined by the nature of the pathogen and the host's immune response.Rapid, accurate, diagnosis is the key to determining zoonotic risk and management options. Currently, Tb in cats is confirmed by culture, IFN-gamma (IFN gamma) release assay (IGRA) or PCR tests. However, there are major limitations with all three methodologies: infected samples fail to culture in up to 50% of cases (despite having ZN+ mycobacteria present); the IGRA cannot always differentiate M. bovis from M. microti; and PCR tests, where available, are very costly. This study aims to improve diagnostic tests for feline Tb that will impact significantly on determining the zoonotic and inter- and intra-species risk of M. bovis and M. microti infections in cats. It will also inform management options, predict survival (likelihood of clearance or latency), and so impact on the long term health of infected cats, their owners, and in-contact domestic and wildlife species. An important output will be a greater understanding of the immune response of domestic cats to infection with M. bovis or M. microti. The project builds upon ongoing studies of the immune response of cats infected with Tb. We have in place a significant bank of samples of serum, plasma and formalin fixed paraffin-embedded tissues (>300) from Tb cats and we will continue to expand this collection. Using these samples we have recently defined the cytokine profile of cats infected with M. bovis or M. microti and shown significant differences between infected and healthy cats, and between M. bovis and M. microti infection. In parallel studies we have also shown significant differences in macrophage responses and granulomatous inflammation in infected cats which are important determinants in the outcome of infectious exposure (MS in preparation). With our industrial partner Biobest we are continuing to evaluate the sensitivity and specificity of the IGRA test. This new PhD project will expand these studies with four major objectives:1) Continue to collect samples from tuberculous cats and healthy controls to expand our biobank and provide additional samples for analysis within this project.2) Measure serum/plasma cytokines using a multiplex cytokine assay to determine whether measurement of additional cytokines (alongside IFN gamma) can improve diagnostic sensitivity and specificity. This will also inform on the immune response to infection with M. bovis and M. microti. 3) Develop, in collaboration with industrial partners, a multiplex antibody detection system that will elucidate the role of the host's humoral immune response to infection.4) Correlate the outcome of (2) and (3) with clinical histories, outcomes and responses to treatment to identify signature profiles that can predict the degree of pathogenicity, the risk of transmission, and the likely response to treatment (where appropriate).The project will enable the student to gain expertise in a wide range of skills and will involve extensive collaboration with Biobest who will be the industrial partner for this work.

结核病是人类和动物关注的一个主要全球问题。在英国，结核病在牛、獾和其他家畜和野生动物物种（包括宠物猫）中日益成为一个问题。我们的研究表明，英国的猫患结核病的风险很高，因为约1%的猫常规组织活检显示与分枝杆菌病一致的组织病理学变化（Gunn-Moore等人，2013年）；其中至少15%是由牛分枝杆菌引起的，19%是由微分枝杆菌（田鼠/啮齿动物杆菌）引起的（Gunn-Moore et al. 2011）。有些猫的牛支原体感染进展极快，在受感染的组织内存在大量生物体并渗出物；鉴于最近发现的猫对人类的人畜共患病风险，这是一个主要问题（Roberts et al. 2014）。我们假设家猫暴露于牛支原体或微支原体的结果以及人畜共患传播的可能性是由病原体的性质和宿主的免疫反应决定的。快速、准确的诊断是确定人畜共患病风险和管理方案的关键。目前，通过培养、IFN- γ (IFN - γ)释放试验（IGRA）或聚合酶链反应（PCR）试验确认猫患结核病。然而，这三种方法都有主要的局限性：在高达50%的病例中，受感染的样本未能培养（尽管存在ZN+分枝杆菌）；IGRA不能总是区分牛分枝杆菌和微分枝杆菌；而聚合酶链反应（PCR）检测在可用的地方非常昂贵。本研究旨在改进猫结核病的诊断测试，这将对确定猫中牛支原体和微支原体感染的人畜共患以及种间和种内风险产生重大影响。它还将为管理方案提供信息，预测存活（清除或潜伏期的可能性），从而影响受感染猫、其主人以及接触的家养和野生动物物种的长期健康。一个重要的成果将是更好地了解家猫对牛分枝杆菌或微分枝杆菌感染的免疫反应。该项目建立在对感染结核病的猫的免疫反应正在进行的研究的基础上。我们已经建立了一个重要的结核病猫血清、血浆和福尔马林固定石蜡包埋组织（bbb300）样本库，我们将继续扩大这一收集范围。利用这些样本，我们最近确定了感染牛分枝杆菌或微分枝杆菌的猫的细胞因子谱，并显示了感染猫和健康猫之间以及牛分枝杆菌和微分枝杆菌感染之间的显著差异。在平行研究中，我们也显示了感染猫的巨噬细胞反应和肉芽肿炎症的显著差异，这是感染暴露结果的重要决定因素（准备中的MS）。我们正在与我们的工业合作伙伴Biobest继续评估IGRA测试的敏感性和特异性。这个新的博士项目将扩展这些研究，主要有四个目标：1)继续从结核病猫和健康对照中收集样本，以扩大我们的生物库，并为本项目提供更多的样本进行分析。2)使用多重细胞因子试验测量血清/血浆细胞因子，以确定是否测量额外的细胞因子（与IFN γ一起）可以提高诊断的敏感性和特异性。这也将有助于了解对牛支原体和微支原体感染的免疫反应。3)与工业伙伴合作开发一种多重抗体检测系统，以阐明宿主对感染的体液免疫反应的作用。4)将(2)和(3)的结果与临床病史、结果和治疗反应联系起来，以确定可以预测致病性程度、传播风险和可能对治疗反应的特征特征（如适用）。该项目将使学生获得广泛技能方面的专业知识，并将涉及与Biobest的广泛合作，Biobest将成为这项工作的工业合作伙伴。