Deciphering the role of host-pathogen-microbiome interactions in the development of bovine digital dermatitis

趾性皮炎（DD）是一种影响全世界反刍动物的疼痛性、传染性足部皮肤病。这种疾病在英国90%以上的奶牛场流行，每年有超过50%的英国奶牛受到影响。除了疼痛和动物福利受损外，DD还与产奶量、采食量和繁殖性能下降有关，据估计，英国乳制品行业每年损失超过7400万英镑。密螺旋体属细菌被认为是与DD相关的主要病原体；然而，该病的发病机制和传播模式尚未阐明。目前的控制策略是通用的，缺乏实质性的证据基础，依赖于外用抗生素和含有重金属（如硫酸铜或福尔马林（致癌物））的洗脚液的经验使用。我们建议开展多学科综合研究，阐明宿主-病原体-微生物组相互作用在DD发展中的作用，提高我们对疾病流行病学的理解，从而为预防疾病提供工具。更具体地说，我们将：确认现有的和鉴定新的基因组标记（snp）和基因组区域与DD抗性相关，并利用独特的现有数据库开发该性状的育种价值。在已知具有DD抗性遗传倾向的动物群体中，描述DD发生前和发展过程中的足部皮肤微生物群落（微生物组）特征，并确定与DD易感性相关的微生物组特征。深入表征健康动物和具有不同DD感染模式和已知DD抗性遗传优点的动物的足部皮肤微生物组。这将有助于更好地了解微生物组对宿主对DD易感性的影响，并有可能确定候选益生菌；宿主遗传和管理对牛足皮肤微生物组的影响也将被描述。研究宿主-病原体-微生物组相互作用在DD病变发展中的作用，并确定感染宿主。我们将量化病原体负担并确定主要感染宿主。我们还将确定具有不同DD抗性遗传优势的动物之间以及具有不同DD感染模式的动物之间的病原体负担和皮肤完整性的差异。在国内和世界范围内，由于牛种群中DD的日益流行所带来的日益严重的福利和成本问题证明了拟议项目的及时性。

Digital dermatitis (DD) is a painful, infectious, foot skin disease affecting ruminants worldwide. The disease is endemic on more than 90% of UK dairy farms and more than 50% of UK dairy cows are affected annually. In addition to pain and compromised animal welfare, DD is also associated with reduced milk yield, feed intake, and reproductive performance, and estimated to cost the UK dairy industry more than £74 million per year. Bacteria of the genus Treponema are considered the main pathogen associated with DD; however, the aetiopathogenesis and transmission patterns of the disease have not yet been elucidated. Current control strategies are generic and lack a substantial evidence base, relying on the empirical use of topical antibiotics and footbathing solutions containing heavy metals, such as copper sulphate, or formalin (carcinogen). We propose here to conduct a multidisciplinary, integrated study that will allow us to elucidate the role of host-pathogen-microbiome interactions in the development of DD, and advance our understanding of the disease's epidemiology, thereby offering tools to prevent the disease. More specifically we will:1. Confirm existing and identify new genomic markers (SNPs) and genomic regions that are associated with resistance to DD and develop breeding values for this trait utilising a unique existing database.2. Characterise the foot skin microbial communities (microbiome) before and during development of DD in a population of animals of known genetic propensity for resistance to DD and identify features of the microbiome associated with susceptibility to DD. We will deliver the first longitudinal, in depth characterisation of the foot skin microbiome in healthy animals and in animals with different DD infection patterns and of known genetic merit for resistance to DD. This will lead to a better understanding of the influence of the microbiome on host susceptibility to DD and has the potential to identify probiotic candidates; host genetic and management effects on the bovine foot skin microbiome will also be described.3. Investigate the role of host-pathogen-microbiome interactions in the development of DD lesions and identify infection reservoirs. We will quantify pathogen burden and identify main infection reservoirs. We will also identify differences in pathogen burden, and skin integrity between animals of different genetic merit for resistance to DD and between animals with different DD infection patterns.Mounting welfare and cost issues brought about by increasing prevalence of DD in bovine populations both nationally and worldwide demonstrate the timeliness of the proposed project.