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

牛乳头缺血性坏死是一种病因不明的严重奶牛疾病，其发病率呈迅速上升趋势。ITN经常导致乳头丢失，这使其成为一个重大的动物福利问题，随后的动物扑杀造成了重大的经济损失。*通过初步的微生物分析，我们发现密螺旋体--通常在牛数字皮炎(DD)皮损中发现的挑剔细菌--与牛ITN高度相关，而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。元基因组学可以阐明疾病相关微生物的多样性和丰富性，最近的高通量测序技术允许对整个DNA补体进行全球鸟枪式元基因组测序，这可能涉及或排除包括细菌、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(参见BBSRC Remit部分)开始描述关系，但现在需要一项更大规模的研究，以确定ITN在英国农场之间和农场内的全面流行，以澄清潜在的风险因素并确定治疗方案。*该项目将与英国乳制品征税委员会(AHDB Dary)合作，后者承认ITN是一种具有重要经济意义的严重新兴疾病。使用系统/数据驱动的生物学和一系列互补的应用方法来对抗ITN。*项目假设：‘有一个特定的微生物联合体负责ITN和II)存在与ITN相关的特定风险因素’。*研究问题：‘a)导致ITN的关键微生物是什么？b)有什么风险因素？’目标和时间表：1)确定ITN病变中的关键相关病原体(1-26个月)。描述潜在病原体的深入数据的鸟枪式元基因组学。详细的组织病理学研究以描述ITN的病因，包括DD螺旋体的免疫组织化学。2)通过邮寄问卷(1-32个月)确定农民报告的与ITN相关的患病率和危险因素。3)开发诊断病原体聚合酶链式反应分析，以进一步分析ITN病变、宿主环境和粪便(24-36个月)。诊断性聚合酶链式反应分析允许对更多的ITN病变进行进一步研究，以确定病因学，然后确定感染源。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)中的风险因素和感染源而量身定做。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(46-48个月)。*牛ITN是一种严重的奶牛乳头疾病，经常导致广泛的自舔，导致整个乳头的破坏。十年前首次报道，在过去两年中，英国报告的病例有所增加，导致严重的动物福利问题，大量受影响的奶牛被扑杀，并造成重大经济损失。*该项目与BBSRC极其相关--它使用系统方法和数据驱动生物学从根本上了解复杂的生物过程，以控制一种重要的新出现的传染病。这将提高这些受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，具有技术开发的潜力。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).