Integrating clinical, data-driven and in-vitro approaches to the study of host-pathogen interactions in bovine digital dermatitis

牛的跛行是一种使人虚弱和痛苦的状况，被描述为奶牛福利受损的最明显指标之一，也是非自愿移除和更换动物的最重要原因之一。没有其他常见的疾病与如此明显的疼痛迹象有关，因此，跛行也损害了公众对该行业的看法。足部疼痛病变占90%以上的奶牛活动能力降低和跛行病例。牛跛行的一个主要原因是数字式皮炎（DD），这是一种痛苦的、传染性的足部皮肤病，影响全世界的反刍动物。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，我们仍然不完全了解这种疾病是如何发展的，以及动物的基因在其中扮演了什么角色。目前的控制策略大多是通用的，缺乏实质性的证据基础，依赖于外用抗生素和足浴溶液的经验性使用；然而，后者通常含有重金属，如硫酸铜或福尔马林（致癌物）。危险化学品的使用和越来越多的证据表明DD密螺旋体具有抗生素耐药性，这意味着目前的控制方法可能对人类健康和环境构成严重威胁。我们假设动物遗传学在DD的发展中起着关键作用，导致动物与病原体相互作用的差异决定了疾病的发展和进展。我们的总体目标是开展一项跨学科的综合研究，以进一步了解导致DD发展的机制，调查动物与病原体的相互作用，并确定最佳的基于证据的育种策略，以增强动物对DD发展的抵抗力和动物从DD中恢复的能力。更具体地说，我们将对动物DD表型的遗传背景进行深入的表征，以确定哪些是关键基因。突变和细胞群在疾病中起着重要作用。此外，我们将利用该疾病的新型实验室模型研究动物-病原体相互作用在DD发展和进展中的作用。最后，我们将利用所有这些新知识来开发先进的策略来控制这种使人衰弱的疾病。对这些机制的透彻理解将支持旨在减少DD发病率和改善DD康复的现代育种规划，并通过帮助确定新的疫苗和药物靶点，为开发有效的靶向治疗提供信息。这将改善动物健康和福利，有可能减少抗菌素耐药性的进一步发展，并支持健康食品的生产。与此相关的非自愿扑杀动物的减少和牛的寿命延长将间接有助于减少温室气体排放并提高该部门的可持续性。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。

Cattle lameness is a debilitating and painful condition, and is described as one of the clearest indicators of compromised welfare in dairy cattle and one of the most important causes of involuntary removal and replacement of animals. No other common condition is associated with such visible signs of pain and, as such, lameness also damages the public's perception of the industry. Painful foot lesions account for more than 90% of reduced cow mobility and lameness cases. One main cause of cattle lameness is Digital Dermatitis (DD) 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, we still don't fully understand how the disease develops and what the role of the animal's genetics in this is. Current control strategies are mostly generic and lack a substantial evidence base, relying on the empirical use of topical antibiotics and foot-bathing solutions; the latter however often contain heavy metals, such as copper sulphate, or formalin (carcinogen). The use of hazardous chemicals and the increasing evidence for antibiotic resistance in DD treponemes mean current control methods may pose a serious threat to human health and environment. We hypothesise that animal genetics play a key role in the development of DD with resulting differences in animal-pathogen interactions determining the development and progression of the disease. Our overarching goal is to conduct an interdisciplinary, integrated study to further our understanding of the mechanisms leading to the development of DD, investigate animal-pathogen interactions, and determine the optimum evidence based breeding strategy to enhance animal resistance to DD development and animal ability to recover from DD. More specifically we will perform an in-depth characterisation of the genetic background of animal DD phenotypes in order to identify what are the key genes, mutations and cell populations playing an important role in the disease. Moreover, we will investigate the role of animal-pathogen interactions in DD development and progression utilising novel laboratory models of the disease. Finally, we will use all these novel knowledge to develop advanced strategies to control this debilitating disease. A thorough understanding of these mechanisms will underpin modern breeding programmes aiming to reduce incidence of DD and improve recovery from DD, and inform the development of effective targeted treatments by helping to identify novel vaccine and drug targets. This will improve animal health and welfare, potentially reducing further development of antimicrobial resistance, and support the production of healthy food. Associated decrease in involuntary culling of animals and increase in cattle longevity will indirectly contribute to reduction of greenhouse gas emissions and improve the sustainability of the sector. 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.