Newton001 Biochemical Investigation of the Enzyme PRMT7 Function in Leishmania spp Parasite Infectivity; Screening Targets for Leishmaniasis Relevance

Newton001 利什曼原虫寄生虫感染性中酶 PRMT7 功能的生化研究；

• 批准号: MR/M02640X/1
• 负责人: Pegine Walrad
• 金额: $ 4.55万
• 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: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM02640X%2F1
• 关键词: Newton001; Biochemical; Investigation; Enzyme; PRMT7

The Leishmaniases are the ninth largest disease burden amongst infectious diseases and the second biggest killer of parasitic diseases next to malaria, threatening one tenth of the world's population. WHO estimates 0.7-1.2 million new cases of cutaneous Leishmaniasis annually while visceral Leishmaniasis infects 200-400,000, killing 10-20% of them. Brazil is stricken by all pathologies of this disease with 30,000 new infections every year. Over 70% of leishmaniasis patients are under 15 years of age. No vaccine exists and there is a growing resistance to available treatments; which are expensive, highly toxic and unsuitable for children. The past decade has seen an increase of epidemics coincident with heightened severity of the disease and an expansion of territory. Despite the urgent need for intervention, leishmaniasis remains a neglected tropical disease. This is largely attributable to its afflicting the poorest of society. Understanding the function and activity of proteins implicated in Leishmania spp. parasite virulence will provide useful insight into new potential ways to combat Leishmaniasis.Leishmania spp. parasites adapt to drastic changes in environments during transmission between insect vectors and human hosts. Developmental changes require the Leishmania parasite cell to interpret changing environmental cues, and to coordinate a swift response for survival. Lifecycle-specific adaptions enable parasite transmission between hosts and perpetuate parasitic infections and diseases. Environmental cues trigger signalling cascades to initiate developmental events. Expressed 'response' proteins enable cellular adaptation to the given environment. Downstream of these signals, specific RNA binding proteins (RBPs) bind mRNAs essential for the cellular response and target them for protein production, storage or degradation. Precise gene regulation coordinates the expression of stage- specific proteins essential for cell adaptation. In this way gene regulation promotes parasite survival and infectivity.Molecular regulators that coordinate the adaptation of these parasites to different host cells and promote parasite infection are critically important to our broader understanding of this disease. The enzyme PRMT7 is a novel regulator of Leishmania virulence. We seek to combine our expertise and facilities to biochemically characterise PRMT7 function and explore how it and its target proteins enable parasite infectivity.The Cruz and Walrad laboratories have complementary expertise and objectives in Leishmania molecular cell biology and transcriptomics. The Cruz lab has an extensive history of molecular characterisation in Leishmania spp. parasites. The Walrad lab has expertise in characterising RNA binding regulatory proteins which enable parasite transmission between hosts.Our collaboration will biochemically characterise the function of the Protein aRginine Methyl Transferase enzyme, PRMT7, its protein targets and how this pathway participates in Leishmania spp. infectivity. PRMT7 is the first Leishmania methylating enzyme to be implicated in host-parasite interactions. Preliminary evidence suggests it may act via modification of regulatory RNA binding proteins, RBPs. The recent MRC NIRG award to the Walrad lab centres on regulatory RBPs involved in Leishmania spp. parasite differentiation to human infectious forms.

利什曼病是传染病中第九大疾病负担，也是仅次于疟疾的第二大寄生虫病杀手，威胁着世界十分之一的人口。WHO估计每年有70 - 120万皮肤利什曼病新发病例，而内脏利什曼病感染20 - 40万人，其中10-20%死亡。巴西受到这种疾病所有病理学的打击，每年有30，000例新感染病例。超过70%的利什曼病患者年龄在15岁以下。没有疫苗，对现有治疗的抵抗力越来越大;这些治疗费用昂贵，毒性很强，不适合儿童。在过去十年中，流行病的增加与疾病的严重性和领土的扩大同时发生。尽管迫切需要进行干预，但利什曼病仍然是一种被忽视的热带疾病。这在很大程度上是因为它影响到社会中最贫穷的人。了解利什曼原虫相关蛋白的功能和活性。寄生虫毒力将提供有用的洞察力，新的潜在的方法来打击利什曼病。寄生虫在昆虫媒介和人类宿主之间传播的过程中适应环境的急剧变化。发育的变化需要利什曼原虫细胞来解释不断变化的环境线索，并协调生存的快速反应。特定于生命周期的适应使寄生虫能够在宿主之间传播，并使寄生虫感染和疾病永久存在。环境线索触发信号级联启动发育事件。表达的“反应”蛋白使细胞能够适应给定的环境。在这些信号的下游，特异性RNA结合蛋白（RBP）结合细胞反应所必需的mRNA，并靶向它们用于蛋白质的产生、储存或降解。精确的基因调控协调细胞适应所必需的阶段特异性蛋白质的表达。通过这种方式，基因调控促进了寄生虫的生存和感染性。分子调节器，协调这些寄生虫适应不同的宿主细胞，促进寄生虫感染是至关重要的，我们更广泛地了解这种疾病。PRMT 7酶是利什曼原虫毒力的一种新型调节剂。我们寻求联合收割机结合我们的专业知识和设施，以生物化学方法研究PRMT 7的功能，并探索它和它的靶蛋白如何使寄生虫感染。Cruz和Walrad实验室在利什曼原虫分子细胞生物学和转录组学方面具有互补的专业知识和目标。Cruz实验室在利什曼原虫属的分子表征方面有着广泛的历史。寄生虫Walrad实验室在表征RNA结合调节蛋白方面具有专业知识，这些蛋白使寄生虫能够在宿主之间传播。我们的合作将生物化学地研究蛋白质a精氨酸甲基转移酶酶PRMT 7的功能，其蛋白质靶点以及该途径如何参与利什曼原虫属。传染性PRMT 7是第一个涉及宿主-寄生虫相互作用的利什曼原虫甲基化酶。初步证据表明，它可能通过修饰调节RNA结合蛋白（RBP）发挥作用。最近MRC NIRG授予Walrad实验室利什曼原虫属的监管RBP中心。寄生虫分化为人类感染形式。

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

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