The Sigma class glutathione transferase from the liver fluke Fasciola hepatica.
The Sigma class glutathione transferase from the liver fluke Fasciola hepatica.
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DOI：
10.1371/journal.pntd.0001666
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发表时间：
2012
影响因子：
3.8
通讯作者：
Brophy PM
中科院分区：
文献类型：
--
作者：
LaCourse EJ;Perally S;Morphew RM;Moxon JV;Prescott M;Dowling DJ;O'Neill SM;Kipar A;Hetzel U;Hoey E;Zafra R;Buffoni L;Pérez Arévalo J;Brophy PM
牲畜的肝吸虫感染每年在全世界造成30亿美元以上的经济损失。该疾病在全世界范围内的牲畜中正在增加，并且是一种重新出现的人类疾病。目前没有商业疫苗，只有一种药物对蠕虫和幼虫有显著疗效。肝吸虫疫苗被认为是必不可少的，因为短期化疗，这是容易产生耐药性，是一个不可持续的选择，在发达国家和发展中国家。蛋白质超家族提供了许多领先的肝吸虫疫苗候选者。谷胱甘肽转移酶（GST）家族的一种新形式，Sigma类GST，与领先的血吸虫疫苗候选者（Sm 28）密切相关，先前已通过肝吸虫中的蛋白质组学揭示，但没有功能特征。在这份手稿中，我们表明，一个纯化的重组形式的F。肝细胞Sigma类GST具有前列腺素合酶活性并影响宿主免疫细胞的活性。免疫细胞化学和蛋白质印迹法显示，该蛋白质存在于吸虫的表面附近，并在卵和新excysted青少年中表达，并存在于成年人的排泄/分泌部分。我们已经评估了使用F的潜力。在一项基于山羊的疫苗试验中，没有发现蠕虫负担的显着减少，但我们发现，通常与肝吸虫感染相关的病理学显着减少。我们证明了F.肝细胞Sigma类GST在宿主-寄生虫相互作用中可能具有从一般解毒和胆汁酸螯合到PGD合酶活性的多功能作用。防治被忽视的寄生虫病对于改善人类和/或其家畜的健康至关重要。揭示宿主-寄生虫相互作用中的关键作用可能支持寄生虫蛋白的疫苗潜力组合。肝片形吸虫在人类及其牲畜中引起全球性疾病，但没有商业疫苗可用。Sigma类谷胱甘肽转移酶（GST）家族的成员长期以来一直被强调为针对寄生扁形虫的疫苗候选物。为此，Sigma类GST目前正在进行II期临床试验，以防止感染。本研究从F.肝吸虫遵循四种工作途径，1）使用底物谱确定其为Sigma类GST，2）评估前列腺素合酶活性及其对宿主免疫细胞的作用，3）将Sigma GST定位于成虫吸虫内和个体发育阶段之间，和4）测量其作为疫苗候选物的潜力。这里介绍的工作表明F.肝细胞瘤Sigma类GST具有关键的宿主-寄生虫作用，我们建议，需要进一步研究纳入疫苗制剂。
Liver fluke infection of livestock causes economic losses of over US$ 3 billion worldwide per annum. The disease is increasing in livestock worldwide and is a re-emerging human disease. There are currently no commercial vaccines, and only one drug with significant efficacy against adult worms and juveniles. A liver fluke vaccine is deemed essential as short-lived chemotherapy, which is prone to resistance, is an unsustainable option in both developed and developing countries. Protein superfamilies have provided a number of leading liver fluke vaccine candidates. A new form of glutathione transferase (GST) family, Sigma class GST, closely related to a leading Schistosome vaccine candidate (Sm28), has previously been revealed by proteomics in the liver fluke but not functionally characterised. In this manuscript we show that a purified recombinant form of the F. hepatica Sigma class GST possesses prostaglandin synthase activity and influences activity of host immune cells. Immunocytochemistry and western blotting have shown the protein is present near the surface of the fluke and expressed in eggs and newly excysted juveniles, and present in the excretory/secretory fraction of adults. We have assessed the potential to use F. hepatica Sigma class GST as a vaccine in a goat-based vaccine trial. No significant reduction of worm burden was found but we show significant reduction in the pathology normally associated with liver fluke infection. We have shown that F. hepatica Sigma class GST has likely multi-functional roles in the host-parasite interaction from general detoxification and bile acid sequestration to PGD synthase activity. Combating neglected parasitic diseases is of paramount importance to improve the health of human populations and/or their domestic animals. Uncovering key roles in host-parasite interactions may support the vaccine potential portfolio of a parasite protein. Fasciola hepatica causes global disease in humans and their livestock but no commercial vaccines are available. Members of the Sigma class glutathione transferase (GST) family have long been highlighted as vaccine candidates towards parasitic flatworms. To this end, a Sigma class GST is currently undergoing phase II clinical trials to protect against infection from the schistosomes. In this study we characterise the protein from F. hepatica following four work pathways that 1) confirm its designation as a Sigma class GST using substrate profiling, 2) assess prostaglandin synthase activity and its effect on host immune cells, 3) localise the Sigma GST within adult fluke and between ontogenic stages and 4) measure its potential as a vaccine candidate. The work presented here shows F. hepatica Sigma class GST to have key host-parasite roles and we suggest, warrants further investigation for inclusion into vaccine formulations.
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影响因子：
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