Regulating the trans-regulators: Investigating the PRMT7 molecular pathway as an epigenetic regulator of Leishmania spp. virulence

调节反式调节因子：研究 PRMT7 分子途径作为利什曼原虫属的表观遗传调节因子。

• 批准号: MR/N017633/1
• 负责人: Pegine Walrad
• 金额: $ 34.34万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN017633%2F1
• 关键词: Regulating; trans; regulators; Investigating; PRMT7

Species of Leishmania threaten 350 million people worldwide on four continents. The Leishmaniases are the second deadliest parasitic disease and all pathologies of this diverse disease are present in Brazil. 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 and Brazilian governments are committed to the World Health Organisation's recent call to further support Neglected Tropical Disease research.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 by 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 mRNA regulation. 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. We have recently isolated a major control panel "Regulator" protein, PRMT7, which controls Leishmania parasite virulence in mammalian infections. Very few Leishmania regulator proteins have yet been identified and this finding represents a major leap forward to isolate and examine this regulatory pathway and block parasite virulence. To study the PRMT7 regulation pathway and identify the way this protein functions, we have assembled a team of experts in Leishmania parasite PRMT proteins, RNA regulators and protein interactions. We believe insight into this pathway will enable us to block the parasite from establishing human infections. We have identified some downstream target proteins of PRMT7 and now seek to determine if they are regulated by PRMT7 and whether they participate in Leishmania parasite virulence. Leishmania proteins are different from human proteins; therefore we can use these differences to target Leishmania- specific virulence factors, block their function and block Leishmaniasis from developing. Significant findings will provide insight to Leishmaniasis research as well as diseases caused by related parasites, Chagas Disease and African Trypanosomiasis.We propose to find more regulators of Leishmania spp. virulence using the PRMT7 virulence pathway. We will identify how these regulators function, and test whether any are essential for parasite survival. Essential Regulators could serve as potential drug targets to block Leishmania parasite infection.The novelty and importance of our project is four fold:1. PRMT7 is the only Protein aRginine Methyl Transferase enzyme that has been characterised in Leishmania spp. parasites thus far and it appears to block virulence (Ferreira et al., 2014). 2. Methylation as a protein modification is uncharacterised in Leishmania spp. parasites. 3. Regulatory RNA binding proteins (RBPs) that are important in parasite lifecycle differentiation, human infectivity and virulence are largely unknown in Leishmania spp.4. The 3-dimensional molecular structures of RBPs and mRNA:protein complexes are largely unknown in all parasites and are absent in Leishmania spp.

利什曼原虫威胁着全球四大洲3.5亿人的生命。利什曼病是第二致命的寄生虫病，巴西存在这种不同疾病的所有病理。世界卫生组织估计，目前全球有1200万人感染，每年有100多万新病例。目前没有疫苗，可用的利什曼病治疗受到日益增长的耐药性的威胁，并且经常被发生率和严重程度不断增加的急性流行病所淹没。新的治疗方法和疫苗是迫切需要的，英国和巴西政府致力于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。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;从哺乳动物到白蛉，再通过白蛉叮咬回到哺乳动物。只有某些生命周期阶段形式的利什曼原虫才能感染人类并在人类中存活。利什曼原虫的外观，代谢和毒力的主要变化发生在这些转变，使他们能够生存。利什曼原虫的基因表达几乎完全依赖于mRNA调控。为了应对环境的变化，特定的寄生虫蛋白质结合mRNA并靶向它们产生蛋白质，以指导和促进适应。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。这些蛋白质是利什曼原虫感染的毒力和传播所必需的。我们最近已经分离出一个主要的控制面板“调节器”蛋白，PRMT 7，控制利什曼原虫在哺乳动物感染的毒力。很少有利什曼原虫调节蛋白已被确定，这一发现代表了一个重大的飞跃，分离和检查这一调节途径和阻断寄生虫毒力。为了研究PRMT 7调节途径并确定这种蛋白质的功能方式，我们组建了一个利什曼原虫PRMT蛋白，RNA调节剂和蛋白质相互作用的专家团队。我们相信对这一途径的深入了解将使我们能够阻止寄生虫建立人类感染。我们已经确定了PRMT 7的一些下游靶蛋白，现在试图确定它们是否受PRMT 7的调控，以及它们是否参与利什曼原虫的毒力。利什曼原虫蛋白质与人类蛋白质不同;因此，我们可以利用这些差异来靶向利什曼原虫特异性毒力因子，阻断其功能并阻断利什曼原虫病的发展。这些重要发现将为利什曼病以及相关寄生虫引起的疾病、恰加斯病和非洲锥虫病的研究提供新的思路。使用PRMT 7毒力途径的毒力。我们将确定这些调节器是如何发挥作用的，并测试是否有任何调节器对寄生虫的生存至关重要。必需调节因子可以作为潜在的药物靶点来阻断利什曼原虫感染。PRMT 7是唯一一种在利什曼原虫属中表征的蛋白质a精氨酸甲基转移酶。迄今为止，它似乎可以阻止寄生虫的毒力（Ferreira等人，2014年）。2.甲基化作为蛋白质修饰在利什曼原虫属中未被表征。寄生虫3.调节RNA结合蛋白（RBP）是重要的寄生虫生命周期的分化，人类感染性和毒力在利什曼原虫spp.4在很大程度上是未知的。RBP和mRNA的三维分子结构：蛋白质复合物在很大程度上是未知的，在所有寄生虫和利什曼原虫属不存在。

项目成果

High speed, three-dimensional imaging reveals chemotactic behavior specific to human-infective Leishmania parasites

高速三维成像揭示了人类感染性利什曼原虫寄生虫特有的趋化行为

• DOI: 10.1101/2020.07.30.220541
• 发表时间: 2020
• 作者: Findlay R

Kinetoplastid cell biology and genetics, from the 2020 British Society for Parasitology Trypanosomiasis and Leishmaniasis symposium, Granada, Spain.

• DOI: 10.1017/s0031182021000998
• 发表时间: 2021-09
• 期刊: Parasitology
• 影响因子: 2.4
• 作者: Walrad PB;Field MC;Navarro M;Robinson DR
• 通讯作者: Robinson DR

Post-translational epigenetics: PRMT7 regulates RNA-binding capacity and protein stability to control Leishmania parasite virulence

翻译后表观遗传学：PRMT7 调节 RNA 结合能力和蛋白质稳定性以控制利什曼原虫寄生虫毒力

• DOI: 10.1101/736736
• 发表时间: 2019
• 作者: Ferreira T

Arginine Methyltransferases as Regulators of RNA-Binding Protein Activities in Pathogenic Kinetoplastids.

• DOI: 10.3389/fmolb.2021.692668
• 发表时间: 2021
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5
• 作者: Campagnaro GD;Nay E;Plevin MJ;Cruz AK;Walrad PB
• 通讯作者: Walrad PB

Protein methyltransferase 7 deficiency in Leishmania major increases neutrophil associated pathology in murine model.

• DOI: 10.1371/journal.pntd.0009230
• 发表时间: 2021-03
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Alcoforado Diniz J;Chaves MM;Vaselek S;Miserani Magalhães RD;Ricci-Azevedo R;de Carvalho RVH;Lorenzon LB;Ferreira TR;Zamboni D;Walrad PB;Volf P;Sacks DL;Cruz AK
• 通讯作者: Cruz AK