Understanding inflammatory processes in ovine footrot to inform rational vaccine design

蹄病是影响英国和世界各地绵羊健康和福利的最重要疾病之一，并影响养羊业的生产力和盈利能力。它是羊的五种最重要的疾病之一，在全球范围内影响着最贫困农民的收入。在英国，每年大约有1400万只羊患上蹄病。足癣是由细菌侵入足部皮肤引起的，会引起疼痛和肿胀。在严重的情况下，蹄角囊，脚的坚硬外表面，与下面的敏感活组织分离，就像指甲从手指上脱落一样。受影响的羊可以用抗生素注射治疗，但要做到这一点，羊必须被抓住。羊是可怕的动物，被抓住和处理时会感到非常紧张，所以尽管治疗对它们的健康和福利有好处，但抓住它们进行治疗的行为也会降低它们的福利; 1400万次治疗意味着很多非常紧张的羊。如果绵羊不接受治疗，它们会体重减轻，跛足一段时间，而且不太可能怀孕。如果他们有羔羊，他们生产的牛奶就少了，所以不能喂养他们的羔羊和那些没有跛脚的母羊，也影响了他们的盈利能力。我们知道，在疾病早期注射抗生素治疗会在几天内迅速恢复。然而，从长远来看，我们希望停止使用抗生素治疗农场动物，以便我们降低抗生素耐药性的风险，并避免抗生素存在于供人类食用的牲畜中。此外，我们希望减少羊的压力，避免需要捕捉和治疗跛脚羊。理想情况下，我们宁愿通过接种疫苗来预防疾病，而不是治疗疾病。有一种疫苗可以帮助控制足癣，但只有不到10%的英国农民使用这种疫苗：它既不持久（最多5个月），也不是很有效（最多60%有效）。这种缺乏有效性被认为是由于未能刺激最佳可能的宿主免疫应答。我们的研究将帮助我们了解绵羊如何在感染的早期阶段对引起蹄病的细菌作出反应，并最终有助于开发预防疾病的替代方法，包括长期的新疫苗。我们将通过研究羊脚的局部免疫防御来做到这一点，免疫系统如何识别引起足炎的细菌以及对这些细菌的免疫反应。此外，我们还将研究导致疾病的细菌菌株之间的关系，以及某些菌株与疾病相关的可能性。我们认为，当绵羊的免疫系统对细菌反应过度时，可能会发生蹄病，就像人类对牛奶的不耐受一样，当我们的肠道对牛奶蛋白质产生反应时，它不应该。或者，这可能是由于缺乏对炎症反应的调节，导致对周围组织的过度附带损伤。如果我们是正确的，那么这将解释为什么抗生素在帮助从蹄病中恢复方面如此出色-因为它们杀死细菌，从而降低绵羊的免疫反应。我们将能够看到这一点，通过研究组织样本取自羊脚的影响和未受影响的蹄。我们还将使用从健康绵羊身上采集的组织样本，我们将在实验室中培养这些样本，并将其暴露于导致蹄病的细菌中。通过这个项目的结束，我们将能够更好地解释如何引起足炎的临床症状，以及免疫系统如何对此做出贡献。这将有助于为疾病管理和最终预防疾病的新方法提供信息。

Footrot is one of the most important diseases affecting the health and welfare of sheep in the UK and throughout the world, and impacts on productivity and profitability within the sheep industry. It is in the top five most important diseases of sheep and globally affects the income of the poorest farmers. Approximately 14 million sheep get footrot in the UK each year. Footrot is caused by bacteria that invade the skin of the foot, and cause pain and swelling. In severe cases, the hoof horn capsule, the hard outer surface of the foot, separates from the underlying and sensitive living tissue, rather like a fingernail coming away from the finger. Affected sheep can be treated with an antibiotic injection, however to do this sheep have to be caught. Sheep are fearful animals and are very stressed by being caught and handled, so although it is good for their health and welfare to be treated, the very act of catching them to administer the treatment also reduces their welfare; 14 million treatments means a lot of very stressed sheep. If sheep are left untreated they lose weight, remain lame for some time and are less likely to become pregnant. If they do have lambs they produce less milk and so cannot feed their lambs as well as those ewes that are not lame, as well as impacting on their profitability. We know that treatment by antibiotic injection early in disease leads to dramatic recovery within a few days. In the long term however, we want to stop using antibiotics to treat farm animals so that we reduce the risk of antibiotic resistance and avoid antibiotics being present in livestock farmed for human consumption. In addition, we want to reduce stress in sheep and avoid the need to catch and treat lame sheep. Ideally, rather that treating disease, we would prefer to prevent disease by vaccination. There is a vaccine available to assist in control of footrot, but less than 10% of UK farmers use this vaccine: it is neither long lasting (5 months maximum) nor very effective (60% effective at best). This lack of effectiveness is thought to be due to a failure to stimulate the best possible host immune response. Our research will help us to understand how sheep respond to the bacteria that cause footrot during the very early stages of infection, and will ultimately help in the development of alternative approaches to preventing disease, including a new vaccine in the longer term.We will do this by studying the local immune defences in the sheep foot, how the bacteria causing footrot are recognised by the immune system and the immune response to these bacteria. In addition, we will investigate the relationships between individual strains of the bacterium that causes disease and the potential for certain strains to be associated with disease. We think that footrot might occur when the sheep immune system responds too much to the bacteria, rather like human intolerance to milk, when our gut reacts to milk proteins when it should not. Alternatively, this could be due to lack of regulation of the inflammatory response leading to excessive collateral damage to the surrounding tissues. If we are right, then this will explain why antibiotics are so good at aiding recovery from footrot - because they kill the bacteria and so reduce the sheep immune response. We will be able to see this by studying tissue samples taken from the feet of sheep affected and unaffected with footrot. We will also use tissue samples taken from healthy sheep that we will culture in the laboratory and expose to bacteria that cause footrot. By the end of this project we will be able to explain better how the clinical signs of footrot are caused and how the immune system contributes to this. This will help to inform on new approaches to disease management and ultimately disease prevention.