The interplay between host and pathogen genetics in the increasing incidence of bovine tuberculosis

宿主和病原体遗传学之间的相互作用导致牛结核病发病率增加

• 批准号: BB/E018335/1
• 负责人: Elizabeth Glass
• 金额: $ 66.09万
• 依托单位: Roslin Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE018335%2F1
• 关键词: interplay; between; host; pathogen; genetics

Tuberculosis (TB) is an infectious, respiratory disease of humans and animals caused by several species of the Mycobacteriaceae family of bacteria. Mycobacterium bovis (M. bovis) is the bacterium that causes TB in cattle (bovine TB) and a wide range of other mammals, including wild animal species such as badgers in the UK and Ireland and possums in New Zealand. They can act as natural reservoirs of M. bovis infection, posing a major impediment to eradication of bovine TB from cattle. Bovine TB presents a barrier to local, national and international free trade with annual economic costs estimated at ~$3 billion worldwide. Bovine TB has existed in the UK and Ireland for centuries and is of growing importance to the UK rural economy. It has a complex biology, involving transmission between and within populations of cattle and populations of wildlife, and still causes a number of human infections annually. Despite sustained and costly implementation of an eradication programme since the 1950s, based on regular testing of cattle, slaughter of test positive cattle, inspection of carcases at the slaughterhouse and crippling restrictions on movements from infected herds, bovine TB has not been eradicated. An acceptable bovine TB vaccine for use in cattle or wildlife is several years away. Despite intensive research on disease detection, on new vaccine candidates and on control of wildlife populations, there has been a largely unexplained increase in TB over the last 15 years, with TB spreading to new areas. Alternative control approaches need to be considered. This proposal will test our hypothesis: the outcome of infection with TB is influenced both by the genetics of the host and the molecular subtype of the pathogen. There is compelling evidence from extensive studies in several species, including humans, mice and deer, to suggest that susceptibility to TB is influenced by the genetics of the animal and that resistance to TB can be inherited. New genetic markers and high-throughput technologies allow us to detect differences in the genetic make-up of individual animals. We initially propose to link two existing datasets, one recording pedigree data (cattle parentage and offspring), the other containing test results for individual animals. We will investigate whether calves of certain bulls are more likely to develop TB. This will provide evidence that susceptibility to TB in cattle is inherited. We will then use the database of animal, slaughterhouse and laboratory test results to select cattle that have bovine TB (cases) and identify other cattle in the same herd, of the same age etc., which should be equally exposed to TB, but are TB negative (controls) and take blood or tissue samples from >500 TB cases and >500 non-TB controls and extract DNA. A high-density panel of 10,000 cattle genetic markers will be applied to this DNA, to investigate whether variation in certain cattle genes is associated with TB cases. This will identify genetic markers associated with TB resistance. New methods to detect different subtypes of TB bacteria have been developed and we will investigate whether the subtype of TB influences the outcome of TB infection in cattle, including the TB test result. Maybe some TB strains are more difficult to detect, with current tests, than others. Potential outcomes include: 1) fundamental insight into the host genetic component to the risk of acquiring TB and the influence of pathogen strain, 2) new light on immune mechanisms which could be exploited to improve diagnosis and vaccine strategies, 3) the possibility of breeding cattle for increased TB resistance. This is a collaboration between Roslin Institute, the UK's leading research institute for animal genetics and Queen's University Belfast, which has an international reputation for research on bovine TB. It is an innovative, multidisciplinary research proposal that exploits recent scientific developments and technical advances to investigate bovine TB.

结核（TB）是一种由分枝杆菌科细菌引起的人类和动物的传染性呼吸道疾病。牛分枝杆菌（M. bovis）是引起牛（牛结核）和许多其他哺乳动物（包括英国和爱尔兰的獾和新西兰的负鼠等野生动物物种）结核病的细菌。它们可以作为牛分枝杆菌感染的天然宿主，对从牛中根除牛结核病构成重大障碍。牛结核病对地方、国家和国际自由贸易构成障碍，每年在全世界造成约30亿美元的经济损失。牛结核病已经在英国和爱尔兰存在了几个世纪，并且对英国农村经济越来越重要。它具有复杂的生物学特性，涉及牛和野生动物种群之间和种群内部的传播，并且每年仍导致许多人类感染。尽管自20世纪50年代以来持续和昂贵地实施了一项根除规划，其基础是对牛进行定期检测、屠宰检测呈阳性的牛、在屠宰场检查尸体以及对受感染畜群的活动进行严格限制，但牛结核病尚未根除。用于牛或野生动物的可接受的牛结核病疫苗还需要几年的时间。尽管在疾病检测、新的候选疫苗和野生动物种群控制方面进行了深入的研究，但在过去15年中，结核病出现了很大程度上无法解释的增长，结核病向新的地区蔓延。需要考虑其他控制方法。这一建议将验证我们的假设：结核感染的结果受到宿主遗传和病原体分子亚型的双重影响。对包括人类、老鼠和鹿在内的几个物种进行的广泛研究提供了令人信服的证据，表明对结核病的易感性受到动物遗传的影响，对结核病的耐药性可以遗传。新的遗传标记和高通量技术使我们能够检测到个体动物基因组成的差异。我们最初建议链接两个现有的数据集，一个记录谱系数据（牛的父母和后代），另一个包含单个动物的测试结果。我们将调查某些公牛的小牛是否更容易患结核病。这将提供证据证明牛对结核病的易感性是遗传的。然后，我们将使用动物、屠宰场和实验室检测结果数据库，选择患有牛结核病（病例）的牛，并在同一畜群中确定年龄相同的其他牛，这些牛应该同样暴露于结核病，但结核病阴性（对照），并从500例结核病病例和500例非结核病对照中采集血液或组织样本并提取DNA。一个由1万头牛遗传标记组成的高密度小组将应用于这种DNA，以调查某些牛基因的变异是否与结核病病例有关。这将确定与结核病耐药性相关的遗传标记。已经开发了检测不同结核细菌亚型的新方法，我们将调查结核亚型是否影响牛结核感染的结果，包括结核检测结果。也许用目前的检测方法，有些结核菌株比其他菌株更难检测。潜在的结果包括：1)对获得结核病风险的宿主遗传成分和病原体菌株的影响有了基本的了解；2)对免疫机制有了新的认识，可用于改进诊断和疫苗策略；3)可能培育出提高结核病耐药性的牛。这是英国领先的动物遗传学研究所罗斯林研究所和贝尔法斯特女王大学之间的合作，贝尔法斯特女王大学在牛结核病研究方面享有国际声誉。这是一项创新的多学科研究计划，利用最近的科学发展和技术进步来调查牛结核病。

项目成果

Additional file 3: of Fine-mapping host genetic variation underlying outcomes to Mycobacterium bovis infection in dairy cows

附加文件 3：精细定位奶牛牛分枝杆菌感染的宿主遗传变异

• DOI: 10.6084/m9.figshare.c.3810310_d3
• 发表时间: 2017
• 作者: S. Wilkinson

Additional file 2: of Fine-mapping host genetic variation underlying outcomes to Mycobacterium bovis infection in dairy cows

附加文件 2：精细定位奶牛牛分枝杆菌感染的宿主遗传变异

• DOI: 10.6084/m9.figshare.c.3810310_d2
• 发表时间: 2017
• 作者: S. Wilkinson

Additional file 5: of Fine-mapping host genetic variation underlying outcomes to Mycobacterium bovis infection in dairy cows

附加文件 5：精细定位奶牛牛分枝杆菌感染的宿主遗传变异

• DOI: 10.6084/m9.figshare.c.3810310_d5
• 发表时间: 2017
• 作者: S. Wilkinson

Hui and Walter's latent-class model extended to estimate diagnostic test properties from surveillance data: a latent model for latent data.

• DOI: 10.1038/srep11861
• 发表时间: 2015-07-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bermingham ML;Handel IG;Glass EJ;Woolliams JA;de Clare Bronsvoort BM;McBride SH;Skuce RA;Allen AR;McDowell SW;Bishop SC
• 通讯作者: Bishop SC

Additional file 6: of Fine-mapping host genetic variation underlying outcomes to Mycobacterium bovis infection in dairy cows

附加文件 6：精细定位奶牛牛分枝杆菌感染的宿主遗传变异

• DOI: 10.6084/m9.figshare.c.3810310_d6
• 发表时间: 2017
• 作者: S. Wilkinson