Bovine ischaemic teat necrosis: combating a severe, emerging disease of economic importance

牛缺血性乳头坏死（ITN）是一种严重的奶牛疾病，病因不明，发病率迅速上升。ITN经常导致动物损失，使其成为一个重大的动物福利问题，随后的动物扑杀造成重大的经济损失。*通过初步的微生物学分析，我们确定了密螺旋体（通常在牛数字性皮炎（DD）病变中发现的挑剔细菌）与牛ITN的高度关联，同时没有发现疱疹病毒或乳头瘤病毒的证据。* ITN的病因需要进一步澄清。宏基因组学可以阐明疾病相关微生物的多样性和丰度，最近的高通量测序技术允许对整个DNA补体进行全球散弹枪宏基因组测序，这可以暗示或排除包括细菌、病毒和真菌在内的一系列微生物的贡献。*虽然一项试点流行病学研究（见BBSRC研究范围部分）开始描绘关系，但现在需要一项更大的研究来确定英国农场间和农场内ITN的全面流行情况，以澄清潜在的风险因素并确定治疗方案。*该项目将与英国乳业征税委员会（AHDB Dairy）合作，该委员会认识到ITN是一种具有经济重要性的严重新兴疾病，将使用系统/数据驱动的生物学以及一系列互补的应用方法来对抗ITN。*项目假设：“i)有一个特定的微生物联合体负责ITN； ii)有与ITN相关的特定风险因素”。*研究问题：“a)导致ITN及其相关感染宿主的主要微生物是什么？ b)风险因素是什么？”目标和时间表：1)确定ITN病变的关键相关病原体（1-26个月）。Shotgun宏基因组学用于描述潜在病原体的深度数据。详细的组织病理学研究，以描述ITN的病因，包括免疫组织化学的DD螺旋体。2)通过邮寄问卷（1-32个月）确定农民报告的ITN患病率和相关风险因素。生成全面的流行病学数据，确定风险因素，以便制定潜在的控制方法/准则。3)发展诊断性病原体PCR检测，进一步分析ITN病变、宿主环境和粪便（24-36个月）。诊断性PCR检测允许对更多的ITN病变进行调查，进一步划定病因，然后确定感染库。4)使用新的体外方法来控制和/或治疗疾病（33-43个月）。针对1)中确定的关键病原体、2)和3)中确定的危险因素和感染宿主量身定制。包括新型消毒剂/防腐剂/抗生素的病原体敏感性测试或对设备/环境净化的调查。5)论文撰写（第46-48个月）。*牛ITN是奶牛的一种严重的乳头疾病，经常导致大量的自舔导致整个乳头的破坏。十年前首次报道，在过去的两年里，英国报告的病例有所增加，导致了严重的动物福利问题，大量受影响的奶牛被淘汰，造成了巨大的经济损失。*该项目与BBSRC非常相关——它使用系统方法和数据驱动生物学从根本上理解复杂的生物过程，以控制一种重要的新兴传染病。这将提高这些管理动物的动物健康和福利，并减少食物链中的浪费，加强粮食安全，具有技术发展的潜力。还涉及与用户/利益相关者的合作研究，为政策/实践提供信息（AHDB乳业）。

Bovine ischaemic teat necrosis (ITN) is a severe disease of dairy cattle with unknown aetiology and is rapidly increasing in prevalence. ITN frequently results in teat loss making it a substantial animal welfare issue with subsequent animal culling causing substantial economic losses.*Through preliminary microbiological analyses we identified a high association for treponemes, fastidious bacteria typically found within bovine digital dermatitis (DD) lesions, with bovine ITN whilst finding no evidence for herpesvirus or papillomavirus. *The aetiology of ITN requires further clarification. Metagenomics can clarify diversity and abundance of disease associated microorganisms and recent high throughput sequencing technology allows global shotgun metagenomic sequencing of entire DNA complements which can implicate or rule out the contribution of a range of microorganisms including bacteria, viruses and fungi. *Whilst a pilot epidemiological study (see BBSRC remit section) begins to delineate relationships, a larger study is now needed to ascertain comprehensive between and within farm prevalence of ITN for the UK, to clarify the underlying risk factors and identify treatment options.*This project would partner with the UK Dairy Levy Board (AHDB Dairy), who recognise ITN as a severe emerging disease of economic importance, to use systems/data driven biology together with a range of complementary applied approaches to combat ITN.*Project hypotheses: 'i) there is a specific microbial consortium responsible for ITN & ii) there are specific risk factors associated with ITN'.*Research questions: 'a) what are the key microorganisms responsible for ITN & their associated infection reservoirs & b) what are the risk factors?' Aims and timelines:1) Identify key associated pathogens in ITN lesions (Months 1-26). Shotgun metagenomics for in depth data describing potential pathogens. Detailed histopathology studies to delineate ITN aetiology including immunohistochemistry of DD treponemes.2) Determine farmer reported prevalence and risk factors associated with ITN via postal questionnaire (Months 1-32). Generate comprehensive epidemiological data and enable risk factor identification allowing for potential control methods/guidelines to be developed.3) Develop diagnostic pathogen PCR assays to analyse further ITN lesions, the host environment and faeces (Months 24-36). Diagnostic PCR assays allow greater numbers of ITN lesions to be investigated further delineating aetiology and then to identify infection reservoirs.4) Use novel in vitro approaches towards control and/or treatment of disease (Months 33-43). Tailored to key pathogens identified in 1), risk factors and infection reservoirs in 2) and 3). To include pathogen susceptibility testing of novel disinfectants/antiseptics/antibiotics or investigations into equipment/environment decontamination.5) Thesis write up (Months 46-48).*Bovine ITN is a severe teat disease of dairy cattle and frequently results in extensive self-licking leading to destruction of the entire teat. First reported ten years ago, in the last two years there has been an increase in UK reported cases, resulting in severe animal welfare issues, a substantial number of affected cows culled and substantial economic losses.*This project is extremely BBSRC relevant - it uses systems approaches and data driven biology to fundamentally understand complex biological processes to control an important emerging infectious disease. This should increase both animal health and welfare of these managed animals and reduce waste in the food chain strengthening food security with potential for technology development. Also involves collaborative research with users/stakeholders to inform policy/practice (AHDB Dairy).