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

14-ATC2 - 基于疫苗的养殖反刍动物片形吸虫病控制（TSB App

• 批准号: BB/M018369/1
• 负责人: Kevin Gough
• 金额: $ 12.81万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM018369%2F1
• 关键词: 14; ATC2; Vaccination; based; control

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.

F.肝吸虫病是肝片吸虫病的病因，肝片吸虫病是一种经济上重要的牛和羊的寄生虫病，它是全世界估计7亿动物慢性肝感染的病因。据估计，感染导致全球每年损失20亿美元，原因是牲畜死亡、生产力下降和本应进入人类食物链的动物产品被淘汰。据估计，这种感染对英国工业造成的成本约为肉牛每年1400万英镑，奶牛每年1350万英镑，绵羊每年310万英镑，尽管这些肯定是保守的，并且仅与直接损失有关。拟议的项目是一个工业化前的研究项目，将使我们能够验证F的重要组成部分的集合。可以组合成亚单位疫苗制剂以保护反刍动物免受该病原体的感染。感染F.肝吸虫病是通过摄入被寄生囊蚴污染的水或植物而获得的，寄生囊蚴包囊以产生新包囊化的幼虫（NEJ），这些幼虫穿过肠和腹膜腔迁移到肝脏并发育成性成熟的雌雄同体成虫。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。这些寄生虫导致奶牛产奶量减少、生育力差、围产期损失高以及慢性体重减轻。急性疾病会导致绵羊因出血和肝脏损伤而突然死亡。吸虫感染的控制严重依赖于有限数量的驱虫化合物，由于其广泛且经常不加区别的使用，导致了与耐药性相关的问题。在食用动物中使用这些药物也引起了新的关注，最近的立法禁止在牛奶用于食物链的奶畜中使用四种主要类别的这些药物。最可行的替代药物治疗是接种抗肝片吸虫病疫苗。目前还没有市售的疫苗制剂可用于控制F。肝。将商业疫苗推向市场的延迟是寄生虫复杂的生命周期，其庞大的基因组和复杂的生物学以及其逃避宿主免疫的策略的结果。F.众所周知，寄生虫改变宿主的免疫反应，从而使针对它的攻击转向，这可能损害并最终杀死寄生虫。这些策略采用许多称为免疫调节剂的分子。此外，针对这种寄生虫的自然发生的免疫应答通常对宿主提供有限的保护。我们现在知道，完全的保护将由免疫系统的两个不同的武器提供抗体和细胞武器。该项目旨在研究i）在显示吸虫负担水平变化的动物中对该生物体的抗体和细胞免疫应答，以及ii）一组新的最近鉴定的免疫调节剂蛋白，由F.可能抑制宿主免疫反应的病毒。目的i）将通过利用抗F的抗体的能力的选择方法进行。我们将测试受感染动物对这些肽的反应，以确定它们的有用性。目的ii）将使用申请人实验室产生的一组新型免疫调节剂，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，将评价最有可能配制成亚单位疫苗制剂的潜在候选疫苗，这些疫苗制剂将显示预防感染或减少蠕虫负荷的功效。我们的项目将受益于将一系列蛋白质/肽纳入最终的疫苗制剂，呈递刺激最佳Th1/Th2应答的抗原，以及克服寄生虫免疫抑制。

项目成果

Fasciola hepatica infection reduces Mycobacterium bovis burden and mycobacterial uptake and suppresses the pro-inflammatory response.

• DOI: 10.1111/pim.12326
• 发表时间: 2016-07
• 期刊: Parasite immunology
• 影响因子: 2.2
• 作者: Garza-Cuartero L;O'Sullivan J;Blanco A;McNair J;Welsh M;Flynn RJ;Williams D;Diggle P;Cassidy J;Mulcahy G
• 通讯作者: Mulcahy G

Fasciola hepatica, TGF-ß and host mimicry: the enemy within.

肝片形吸虫、TGF-β 和宿主拟态：内部的敌人。

• DOI: 10.1016/j.mib.2018.09.002
• 发表时间: 2018
• 期刊: Current opinion in microbiology
• 影响因子: 5.4
• 作者: Musah-Eroje M

A rapid IL-17 response to Cryptosporidium parvum in the bovine intestine.

• DOI: 10.1016/j.vetimm.2017.07.009
• 发表时间: 2017-09
• 期刊: Veterinary immunology and immunopathology
• 影响因子: 1.8
• 作者: Drinkall E;Wass MJ;Coffey TJ;Flynn RJ
• 通讯作者: Flynn RJ

A host-independent role for Fasciola hepatica transforming growth factor-like molecule in parasite development.

肝片形吸虫转化生长因子样分子在寄生虫发育中的宿主独立作用。

• DOI: 10.1016/j.ijpara.2020.11.005
• 发表时间: 2021
• 期刊: International journal for parasitology
• 影响因子: 4
• 作者: Musah-Eroje M

Myeloid-derived suppressor cell, arginase-1, IL-17 and cl-CD95L: an explosive cocktail in lupus?

骨髓源性抑制细胞、精氨酸酶-1、IL-17 和 cl-CD95L：狼疮中的爆炸性混合物？

• DOI: 10.21037/atm.2016.12.35
• 发表时间: 2016
• 期刊: Annals of translational medicine
• 作者: Flynn RJ