14-ATC2 - Vaccination based control of fasciolosis in farmed ruminants (TSB App # 45264-298219)

肝炎F.是引起片形吸虫病的原因，片形吸虫病是牛和羊的一种重要的经济寄生虫病，是全世界估计有7亿只动物慢性肝脏感染的原因。据估计，由于牲畜死亡、生产力下降和本该进入人类食物链的动物产品遭到拒绝，感染导致全球每年损失20亿美元。据估计，这种感染给英国工业造成的损失在肉牛中约为每年1400万英镑，在奶牛中约为每年1350万英镑，在绵羊中约为每年310万英镑，尽管这些肯定是保守的，只涉及直接损失。拟议的项目是一个工业化前的研究项目，它将使我们能够验证肝炎F.的一系列重要成分，这些成分可以组合成亚单位疫苗配方，以保护反刍动物免受这种病原体的感染。肝炎F.的感染是通过摄入被寄生囊蚴污染的水或植被而获得的，这些囊蚴囊出产生新囊出的幼虫（nej），这些幼虫通过肠道和腹膜腔迁移到肝脏，并发育成性成熟的雌雄同体成年虫。成虫将卵释放到胆管中，这些卵被运送到肠道，并通过粪便释放到环境中。这些寄生虫导致产奶量减少、生育力差和围产期损失高，以及牛的慢性体重下降。急性疾病会导致绵羊因出血和肝损伤而突然死亡。控制吸虫感染严重依赖于数量有限的驱虫化合物，由于它们的广泛使用和经常滥用，导致了与耐药性有关的问题。在食用动物中使用这些药物也引起了人们的关注，最近的立法禁止在奶牛中使用四类主要药物，因为奶牛的牛奶将被运往食物链。最可行的替代药物治疗方法是接种片形吸虫病疫苗。目前市场上还没有疫苗制剂可用于控制肝梭菌。将商业疫苗推向市场的延迟是由于寄生虫的复杂生命周期，其庞大的基因组和复杂的生物学，以及它用来逃避宿主免疫的策略。众所周知，肝梭菌可以改变宿主的免疫反应，从而转移针对它的攻击，这些攻击可能会损害并最终杀死寄生虫。这些策略采用了许多称为免疫调节剂的分子。此外，针对这种寄生虫的自然免疫反应通常对宿主提供有限的保护。我们现在知道免疫系统的两个不同的分支抗体和细胞分支将提供全面的保护。该项目旨在描述i)在动物中对这种生物体的抗体和细胞免疫反应，这些反应显示出吸虫负担水平的变化，ii)最近发现的一组新的免疫调节蛋白，由肝f产生，可能会抑制宿主的免疫反应。目的i)将通过一种选择方法来进行，该方法利用抗肝梭菌抗体与小蛋白（肽）结合的能力，然后我们将测试受感染动物对这些肽的反应，以确定它们的有效性。Aim ii)将使用申请人实验室生成的一套新的免疫调节剂，将测试其破坏正常宿主免疫功能的能力。这项为期18个月的研究完成后，将评估最有可能制成亚单位疫苗制剂的潜在候选疫苗，这些疫苗将在预防感染或减轻蠕虫负担方面显示效力。我们的项目将受益于将一系列蛋白质/肽纳入最终的疫苗配方，提供刺激最佳Th1/Th2反应以及克服寄生虫免疫抑制的抗原。

F. hepatica is the cause of fasciolosis, an economically important parasitic disease of cattle and sheep which is the cause of chronic liver infection in an estimated 700 million animals worldwide. Infection results in an estimated annual global loss of US$2000 million through livestock mortality, reductions in productivity and condemnation of animal products that should go into the human food chain. Costs of this infection to UK industry is estimated to be around £14M/annum in beef cows, £13.5M/annum in dairy cattle and £3.1M/annum in sheep, although these are most certainly conservative and relate todirect losses only. The proposed project is a pre-industrial research project that will enable us to validate a collection of important components of F. hepatica that could be combined into sub-unit vaccine formulations for protecting ruminants against infection with this pathogen. Infection by F. hepatica is acquired by the ingestion of water or vegetation that is contaminated by parasitic metacercariae which excyst to produce newly excysted juveniles (NEJs) , these migrate across the intestine and peritoneal cavity to the liver and develop into sexually mature hermaphrodite adults. The adults release eggs into the bile ducts, which are transported to the intestine and are released into the environment via faeces. These parasites cause reduced milk yields, poor fertility and high perinatal loses, and chronic weight loss in cattle. Acute disease will cause sudden death from haemorrhage and liver damage in sheep. Control of fluke infection is heavily reliant on a limited number of anthelmintic compounds, which due to their widespread and often indiscriminate use has led to problems associated with drug resistance. There are also emerging concerns regarding the use of these drugs in food production animals, with recent legislation banning the use of four major classes of these drugs in dairy animals where milk is destined for the food chain. The most viable alternative to drug treatment would be vaccination against Fasciolosis. Currently no vaccine preparation is commercially available to control F. hepatica. The delay in bringing a commercial vaccine to market is a result of the complex lifecycle of the parasite, its large genome and complex biology, and the strategies it employs to evade host immunity. F. hepatica is well known to alter the host immune responses thereby deflecting attacks aimed at it which could damage and eventually kill the parasite. These strategies employ a number of molecules termed immunomodulators. Furthermore, the naturally occurring immune responses against this parasite often provide limited protection to the host. We now know that full protection will be offered by the two distinct arms of the immune system the antibody and the cellular arms. This project aims to characterise i) both the antibody and cellular immune response to this organism in animals that show variation in levels of fluke burdens and ii) a novel set of recently identified Immunomodulator proteins, produced by F. hepatica that are likely to suppress the host immune response. Aim i) will be conducted by a selection method exploiting the ability of antibodies against F. hepatica to bind to small proteins (peptides) - we will then test the reaction of infected animals to these peptides to determine their usefulness. Aim ii) will use a novel set of immunomodulators generated in the applicants lab that will be tested for their ability to subvert normal host immune functions. Upon completion this 18 month study will evaluate potential vaccine candidates that have the greatest potential for formulation into subunit vaccine preparations that will show efficacy in either preventing infection or reducing worm burden. Our project will benefit from incorporating a range of proteins/peptides into the final vaccine formulation, presenting antigens that stimulate an optimal Th1/Th2 response as well as overcoming parasite immunosuppression.