Fasciola hepatica extracellular vesicles - the key to parasite control?

片吸虫病是一种常见的、具有重要经济意义的牲畜疾病。它是由一种名为肝片吸虫(又称肝吸虫)的寄生扁虫引起的，它感染了全球超过3亿头牛和2.5亿只羊，导致生产力下降，给全球农业造成了超过30亿美元的损失。该病在英国也很普遍，由于动物条件差以及牛奶和肉类产量大幅下降，仅养牛业每年就损失约2300万GB。尽管传统上被认为是一种牲畜疾病，但肝片吸虫病是一种新出现的人类疾病，据估计，全球有240万人感染。抗肝吸虫感染的首选药物是三氯苯咪唑。然而，就像在我们医院肆虐的抗药性细菌一样，对三氯苯达唑具有抗药性的吸虫现在正在英国/爱尔兰、欧洲大陆和澳大利亚迅速传播。这使得农民几乎没有办法抗击这种疾病，因为大多数剩余的药物对对受感染动物造成最大损害的未成熟吸虫无效。由于预计未来60年英国将爆发史无前例的肝吸虫感染，开发新的肝吸虫控制策略是当务之急。抗药性的蔓延，加上消费者对食品中存在化学残留物的高度担忧，推动了抗片吸虫疫苗的研究。尽管取得了一些早期的成功，但仍然没有商业化的肝片吸虫疫苗。这很可能是由于寄生虫影响宿主免疫反应的惊人能力。片状吸虫是一种成熟的免疫调节器，它引导宿主免疫反应远离对它们最具破坏性的类型-Th1反应-并调节反应，以创造一个优化成功喂养和繁殖的环境-Th2反应。我们已经发现寄生虫释放的特定分子负责这种免疫调节，我们认为针对这些分子的释放可能是寄生虫控制的关键。最近的研究表明，分子可以通过被包装成称为细胞外小泡(EVS)的囊来从一个细胞转移到另一个细胞。我们的合作者Antonio Marcilla博士(巴伦西亚大学)最近发现，电动汽车也是从肝片吸虫中释放出来的，我们现在知道它们含有许多已知的免疫调节剂。因此，我们认为，阻止EV从寄生虫中释放将阻止包装在体内的免疫调节分子转移到宿主免疫细胞。这将使Th1免疫反应占上风，导致寄生虫被驱逐。为了实现这一点，我们将使用一种名为RNA干扰(RNAi)的新技术来“关闭”与EV的包装和释放有关的特定分子。然后，我们将能够确定这种方法是否能增强宿主的免疫反应，并消除寄生虫。这是一个多学科项目，将建立在片吸虫生物学最新发现和技术进步的基础上。因此，我们聚集了一个强大的国内和国际合作者网络，他们将在RNAi(Maule教授)、免疫学(Dalton教授和Donnelly博士)和EV生物学(Marcilla博士)方面提供相当大的支持和专业知识。我们预计，这项研究将产生控制肝吸虫感染的特定目标(通过新药或疫苗)，这些目标将具有商业吸引力，并可转移到其他人和动物的寄生虫感染。

Fasciolosis is a common, and economically important, disease of livestock. It is caused by a parasitic flatworm called Fasciola hepatica (also known as the liver fluke) that infects more than 300 million cattle and 250 million sheep worldwide resulting in losses of over $3 billion to global agriculture through lost productivity. It is also widespread in the UK, and costs the cattle farming industry alone around £23 million each year as a result of poor animal condition and a significant reduction of milk and meat yields. Although traditionally regarded as a disease of livestock, fasciolosis is an emerging disease of humans with an estimated 2.4 million people infected worldwide. The drug of choice against liver fluke infection is triclabendazole. However, just like the drug-resistant bacteria that are wreaking havoc in our hospitals, triclabendazole-resistant fluke are now rapidly spreading throughout the UK/Ireland, continental Europe and Australia. This has left farmers with little to combat the disease as most remaining drugs are ineffective against the immature flukes that cause most damage to the infected animal. With unprecedented outbreaks of liver fluke infection predicted to occur in the UK over the next 60 years, the development of new strategies for F. hepatica control is most urgent. The spread of drug resistance, together with heightened consumer concerns about the presence of chemical residues in food, has fuelled the search for anti-Fasciola vaccines. Despite some early successes there are still no commercially-available vaccines against F. hepatica. This is most likely due to the striking ability of the parasite to influence the host immune response. Fasciola is an accomplished immune-modulator, directing the host immune response away from the type that is most damaging to them - a Th1 response - and regulating the response to create an environment that optimises successful feeding and reproduction - a Th2 response. We have found that specific molecules released by the parasites are responsible for this immune-modulation and we believe that targeting the release of these may be the key to parasite control. Recent research has shown that molecules can be transferred from one cell to another by being packaged into sacs called extracellular vesicles (EVs). Our collaborator Dr Antonio Marcilla (University of Valencia) recently found that EVs are also released from F. hepatica and we now know that they contain many known immunomodulators. Thus, we propose that preventing the release of EVs from the parasite will stop the transfer of the immunomodulatory molecules packaged inside to host immune cells. This will allow a Th1 immune response to prevail leading to expulsion of the parasite. To achieve this we will use a new technique called RNA interference (RNAi) to "switch off" particular molecules that are involved in packaging and release of EVs from the parasite. We will then be able to determine if this approach can give the host`s immune response a boost and eliminate the parasite. This is a multidisciplinary project which will build on recent discoveries in Fasciola biology and advances in technology. As such, we have assembled a strong network of national and international collaborators who will provide considerable support and expertise in RNAi (Prof Maule), immunology (Prof Dalton and Dr Donnelly) and EV biology (Dr Marcilla). We envisage that specific targets will emerge from this research for control of liver fluke infections (by new drugs or vaccines) that will be commercially attractive and transferable to other parasitic infections of humans and animals.