The role of 'parasitism islands' in infection by soil-transmitted helminths

了解土壤传播的蠕虫寄生虫(STH)进化为感染其宿主的机制是开发亟需改进的治疗和控制方法的重要一步。最近发现，STH中与寄生相关的基因(例如，编码操纵宿主免疫反应的蛋白质的基因)在物理上聚集在基因组中，形成“寄生岛”。这些区域与细菌中具有良好特征的致病岛有许多相似之处，我们假设寄生岛在寄生虫感染中具有根本性的重要作用。寄生岛屿为驱虫药和替代治疗策略提供了潜在的目标。结合基于实验室和生物信息学的方法，我们将调查寄生岛的作用和组织，重点是以下问题：寄生岛总体上是寄生虫基因组的特征吗？寄生岛上的基因表达是如何调控的？寄生岛在寄生虫-宿主相互作用中的功能作用是什么？对于实验室中的组件，将使用拉蒂圆线虫模型。这是一个成熟的寄生虫感染实验室模型，也是人类寄生虫的近亲，全世界有6亿人感染这种寄生虫。圆线虫是CRISPR/Cas9技术已经建立的为数不多的寄生线虫之一，我们将使用这些方法来研究基因在寄生岛中的功能作用。我们还将对表观遗传标记进行功能分析，包括研究组蛋白修饰和小RNA在感染不同阶段的毒力热点调控中的作用。基于我们对S.Ratti的发现，我们可能会继续对其他蠕虫物种进行这些方法。这些方法将帮助我们更好地了解寄生虫成功感染宿主所使用的遗传工具箱。

Understanding the mechanisms soil-transmitted helminth parasites (STHs) have evolved to infect their host is an important step towards developing much needed improvements in treatments and control methods. It has recently been discovered that parasitism-associated genes in STHs (e.g. genes coding for proteins that manipulate the host immune response) are physically clustered in the genome into 'parasitism islands'. These regions share many similarities with the pathogenicity islands that are well characterised in bacteria, and we hypothesise that parasitism islands have a fundamentally important role in parasite infection. Parasitism islands offer potential targets for anthelminthic drugs and alternative treatment strategies. Using a combination of lab-based and bioinformatic approaches we will investigate the role and organisation of parasitism islands, focusing on the questions: Are parasitism islands characteristic of parasite genomes in general? How is gene expression regulated in parasitism islands? and what is the functional role of parasitism islands in parasite-host interaction?For the lab-based components, the model Strongyloides ratti will be used. It is a well-established lab model for parasite infection and a close relative of the human parasite S. stercoralis which infects 600 million people worldwide. The Strongyloides parasites are one of the few parasitic nematodes that CRISPR/Cas9 techniques have been established for and we will use these methods to investigate the functional role of genes in parasitism islands. We will also perform functional analysis of epigenetic marks, including investigating the role of histone modifications and small RNAs in the regulation of virulence hotspots at different stages of infection. Based on our findings with S. ratti we may then go on to carry out these methods on other helminth species. Together these approaches will help us to better understand the genetic toolbox used by parasites to successfully infect the host.