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/E018335/2
• 负责人: Elizabeth Glass
• 金额: $ 60.56万
• 依托单位: University of Edinburgh
• 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%2F2
• 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.

结核病(TB)是一种由分枝杆菌科细菌家族的几种细菌引起的人和动物的传染性呼吸道疾病。牛分枝杆菌(M.bovis)是引起牛(牛结核病)和其他多种哺乳动物结核病的细菌，包括英国和爱尔兰的獾和新西兰的负鼠等野生动物物种。它们可以作为牛分枝杆菌感染的天然宿主，对从牛身上根除牛结核病构成了主要障碍。牛结核病是地方、国家和国际自由贸易的障碍，全球每年的经济损失约为30亿美元。牛结核病在英国和爱尔兰已经存在了几个世纪，对英国农村经济的重要性越来越大。它具有复杂的生物学特性，涉及牛与野生动物种群之间和种群内的传播，每年仍会导致一些人感染。尽管自1950年代以来，基于对牛的定期检测、对检测呈阳性的牛的屠宰、对屠宰场的身体检查以及对受感染牛群迁移的严重限制，持续且代价高昂地实施了根除方案，但牛结核病并未被根除。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密集的研究，但在过去15年中，随着结核病传播到新的地区，结核病在很大程度上出现了原因不明的增加。需要考虑其他控制方法。这一提议将检验我们的假设：感染结核病的结果既受宿主的遗传因素影响，也受病原体的分子亚型影响。有令人信服的证据表明，包括人类、小鼠和鹿在内的几个物种的广泛研究表明，对结核病的敏感性受到动物基因的影响，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单个动物的基因构成的差异。我们最初建议连接两个现有的数据集，一个记录系谱数据(牛的亲子关系和后代)，另一个包含对单个动物的测试结果。我们将调查某些公牛的小牛是否更有可能患上结核病。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的数据库来选择患有牛结核病(病例)的牛，并确定同一牛群、相同年龄等的其他牛，这些牛应该同样接触结核病，但结核病阴性(对照)，并从500例结核病病例和500例非结核病对照中提取血液或组织样本，并提取DNA。一个由10,000头牛的高密度遗传标记组成的小组将被应用于这种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。已经开发出检测不同亚型结核病细菌的新方法，我们将调查结核病亚型是否会影响牛的结核病感染结果，包括结核病检测结果。也许，用目前的检测方法，某些结核病菌株比其他菌株更难发现。潜在的结果包括：1)对宿主遗传成分对感染结核病的风险和病原体菌株的影响的基本洞察，2)对可用于改进诊断和疫苗策略的免疫机制的新认识，3)饲养牛以提高对结核病的抵抗力的可能性。这是英国领先的动物遗传学研究机构罗斯林研究所和贝尔法斯特女王大学的合作，后者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方案，利用最新的科学发展和技术进步来研究牛结核病。

项目成果

Genome-wide association study identifies novel loci associated with resistance to bovine tuberculosis.

• DOI: 10.1038/hdy.2013.137
• 发表时间: 2014-05
• 期刊: HEREDITY
• 影响因子: 3.8
• 作者: Bermingham, M. L.;Bishop, S. C.;Woolliams, J. A.;Pong-Wong, R.;Allen, A. R.;McBride, S. H.;Ryder, J. J.;Wright, D. M.;Skuce, R. A.;McDowell, S. W. J.;Glass, E. J.
• 通讯作者: Glass, E. J.

A genetic analysis of interval censored single intradermal comparative tuberculin test data from the bovine tuberculosis control programme in Northern Ireland

对北爱尔兰牛结核病控制计划的间隔删失单一皮内比较结核菌素测试数据进行遗传分析

• 发表时间: 2010
• 作者: Bermingham ML

Estimating heritability, true prevalence and diagnostic test properties for bovine tuberculosis from surveillance data.

根据监测数据估计牛结核病的遗传力、真实患病率和诊断测试特性。

• 发表时间: 2010
• 作者: Bermingham ML

Evidence for genetic variance in resistance to tuberculosis in Great Britain and Irish Holstein-Friesian populations.

• DOI: 10.1186/1753-6561-5-s4-s15
• 发表时间: 2011-06-03
• 期刊: BMC proceedings
• 作者: Bermingham ML;Brotherstone S;Berry DP;More SJ;Good M;Cromie AR;White IM;Higgins IM;Coffey M;Downs SH;Glass EJ;Bishop SC;Mitchell AP;Clifton-Hadley RS;Woolliams JA
• 通讯作者: Woolliams JA

A genomewide association study identifies resistance loci for bovine tuberculosis in the Northern Ireland Holstein Friesian dairy cattle population.

一项全基因组关联研究确定了北爱尔兰荷斯坦弗里斯兰奶牛群体中牛结核病的耐药位点。

• 发表时间: 2011
• 作者: Bermingham ML