Regulation of gene expression in Leishmania parasites: structure, function and post-transcriptional modification of RNA binding proteins

单细胞利什曼原虫在其生命周期中转变为许多不同的形式，以适应非常不同的宿主；从哺乳动物到沙蝇，再通过沙蝇叮咬回到哺乳动物。只有某些生命周期阶段的利什曼原虫才能在人类体内感染和存活。利什曼原虫的外观、新陈代谢和毒力在这些转变期间发生了重大变化，使它们能够存活。利什曼原虫的基因表达几乎完全依赖于信使RNA的调节。作为对环境变化的反应，特定的寄生虫蛋白结合mRNAs，并将其作为蛋白质生产的靶标，以引导和促进适应。控制这些寄生虫适应的蛋白质使它们能够在人体内生存并感染人类。这些蛋白质对于利什曼原虫感染的毒力和传播是必不可少的。利什曼病是第二大致死性寄生虫病。利什曼原虫的物种威胁着全球四大洲的3.5亿人。世界卫生组织估计，目前全球有1200万人感染，每年新增病例超过100万例。目前没有疫苗存在，现有的利什曼病治疗方法受到日益增长的耐药性的威胁，而且往往被发病率和严重性不断增加的急性流行病所淹没。人们迫切需要新的治疗方法和疫苗，英国政府致力于响应世界卫生组织最近的呼吁，进一步支持被忽视的热带病研究。我们已经分离出特定的RNA结合反式调节蛋白，这些蛋白通过精氨酸甲基化来修饰和调节。我们已经证明，负责这种修饰的甲基转移酶水平调节了利什曼原虫的主要感染性和毒力。该项目将重点研究精氨酸甲基化如何修改目标RNA结合蛋白的3D结构、相互作用轮廓和功能，以及这种翻译后修饰如何影响寄生虫的感染性和毒力。从分子水平了解这一表观遗传过程将极大地促进我们对利什曼原虫转录后反式调节的了解。

The single-cell Leishmania parasite transforms into many different forms during its lifecycle to adapt to very different hosts; moving from mammals to sandflies and back to mammals via sandfly bites. Only Leishmania parasites of certain lifecycle stage forms can infect and survive in humans. Major changes to the Leishmania parasite's appearance, metabolism and virulence occur during these transitions that enable them to survive. Gene expression in Leishmania relies almost exclusively upon regulation of messenger RNAs. In response to changes in the environment, specific parasite proteins bind mRNAs and target them for protein production to guide and promote adaptation. Proteins that control the adaptation of these parasites enable them to survive in and infect humans. Such proteins are essential for the virulence and spread of the Leishmania parasite infection. The Leishmaniases are the second deadliest parasitic disease. Species of Leishmania threaten 350 million people worldwide on four continents. The World Health Organisation estimates 12 million people globally are currently infected and over 1 million new cases occur annually. No vaccine currently exists and available Leishmaniasis treatments are threatened by growing resistances and often overwhelmed by acute epidemics that are increasing in occurrence and severity. New treatments and vaccines are desperately needed and the UK government is committed to the World Health Organisation's recent call to further support Neglected Tropical Disease research. We have isolated specific RNA binding trans-regulatory proteins that are modified and regulated through arginine methylation. We have shown that levels of the methyltransferase enzyme responsible for this modification modulate Leishmania major infectivity and virulence. The project will focus on how arginine methylation modifies the 3D structure, interaction profile and function of target RNA binding proteins, and how this post-translational modification affects parasite infectivity and virulence. A molecular-level understanding of this epigenetic process will greatly advance our knowledge of post-transcriptional trans-regulation in Leishmania parasites.