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

结核病（TB）是由分枝杆菌科细菌的几种物种引起的人类和动物的传染性呼吸道疾病。牛分枝杆菌（M. bovis）是导致牛（牛结核病）和广泛的其他哺乳动物（包括野生动物物种，如英国和爱尔兰的獾和新西兰的负鼠）的结核病的细菌。它们可以作为M.牛结核病是从牛身上根除牛结核病的主要障碍。牛结核病对地方、国家和国际自由贸易构成障碍，全世界每年的经济损失估计约为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日益增加。它具有复杂的生物学特性，涉及牛种群和野生动物种群之间和内部的传播，并且每年仍然导致许多人类感染。尽管自1950年代以来，在定期检测牛、屠宰检测阳性牛、在屠宰场检查尸体和严格限制受感染牛群的流动的基础上，持续和昂贵地实施了根除方案，但牛结核病仍未根除。可接受的牛结核病疫苗用于牛或野生动物是几年后。尽管对疾病检测、新的候选疫苗和野生动物种群控制进行了深入研究，但在过去15年中，结核病的增加在很大程度上无法解释，结核病蔓延到了新的地区。需要考虑其他控制方法。这一提议将检验我们的假设：结核病感染的结果受到宿主遗传学和病原体分子亚型的影响。对包括人类、小鼠和鹿在内的几个物种进行的广泛研究有令人信服的证据表明，对结核病的易感性受到动物遗传学的影响，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个体动物遗传组成的差异。我们最初建议将两个现有的数据集连接起来，一个记录系谱数据（牛的父母和后代），另一个包含个体动物的测试结果。我们将调查某些公牛的小牛是否更有可能患结核病。这将为牛对结核病的易感性是遗传的提供证据。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，并识别同一牛群中相同年龄等的其他牛，其应该同等地暴露于TB，但为TB阴性（对照），并从>500个TB病例和>500个非TB对照中采集血液或组织样品并提取DNA。一个由10，000个牛遗传标记组成的高密度小组将应用于该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。目前已开发出检测不同结核菌亚型的新方法，我们将研究结核菌亚型是否会影响牛结核病感染的结果，包括结核病检测结果。也许有些结核菌株比其他菌株更难用现有的检测方法检测出来。可能的成果包括：1）对宿主遗传成分对获得TB的风险和病原体菌株的影响的基本认识，2）可用于改进诊断和疫苗策略的免疫机制的新认识，3）饲养牛以增加TB抗性的可能性。这是英国领先的动物遗传学研究机构罗斯林研究所和在牛结核病研究方面享有国际声誉的贝尔法斯特女王大学之间的合作。这是一项创新的多学科研究提案，利用最新的科学发展和技术进步来调查牛结核病。

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.