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

了解土壤传播蠕虫（STHs）感染宿主的进化机制是开发治疗和控制方法的重要一步。最近发现，STHs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）在基因组中物理聚集成“寄生岛”。这些区域与细菌的致病性岛有许多相似之处，我们假设寄生岛在寄生虫感染中起着重要的作用。寄生岛为驱虫药物和替代治疗策略提供了潜在靶点。利用实验室和生物信息学方法的结合，我们将研究寄生岛的作用和组织，重点关注以下问题：寄生岛是寄生虫基因组的一般特征吗？寄生岛的基因表达是如何调控的？寄生岛在寄主-寄主相互作用中的功能作用是什么？对于基于实验室的组件，将使用圆形线虫模型。它是寄生虫感染的一个成熟的实验室模型，也是人类寄生虫S. stercoralis的近亲，后者在全世界感染了6亿人。圆线虫是为数不多的已建立CRISPR/Cas9技术的寄生线虫之一，我们将利用这些方法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在不同感染阶段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种类的蠕虫进行这些方法。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.