Proteolysis and life cycle progression in Leishmania

利什曼原虫的蛋白水解和生命周期进展

• 批准号: MR/K019384/2
• 负责人: Jeremy Mottram
• 金额: $ 109.97万
• 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%2FK019384%2F2
• 关键词: Proteolysis; life; cycle; progression; Leishmania

Leishmaniasis is a severe disease of humans and one of the world's most neglected diseases, primarily affecting the poor in developing countries. 350 million people are at risk of contracting the disease and it has severe costs in both health and economic terms and drains resources that could be used to promote growth of developing nations. There is no effective vaccine against the disease and chemotherapy is the prime means for reducing the leishmaniasis burden. Unfortunately the drugs available have many limitations and new drugs are desperately needed. Our aim in this programme of work is to characterise key biological processes of Leishmania, the parasite that causes leishmaniasis, and so identify and validate potential drug targets. We have shown that peptidases, enzymes that digest proteins, play central roles in the development of Leishmania and are important in the infectivity and pathogenicity of the parasite. Our work will concentrate on 3 key areas of the biology of the parasite. Firstly, we will identify peptidases that are important for the pathogenesis of the disease and investigate key pathways involved in peptidase function. In particular we shall investigate a process called autophagy (self-cannibalism), which leads to the development of infectious parasites and allows the parasite to live within a mammalian host. We will also investigate the function of a parasite-specific peptidase, metacaspase, which is essential for growth of the parasite but the function of which is unclear. A key approach will be to genetically manipulate important Leishmania genes to find out what role the encoded proteins play in the parasite's infectivity and virulence and to determine whether they might be exploited as drug targets. To achieve this we will develop new methods and research tools for the genetic manipulation of Leishmania. Secondly, we shall investigate the genome variation that occurs in different strains and species of Leishmania. We will sequence the genomes of Leishmania parasites isolated from patients in the Sudan and identify genes that influence the outcome of disease. Finally, we shall use a closely related parasite, the African trypanosome, as a model for investigating the regulation of peptidase function. The African trypanosome is suitable for large scale studies, so we can utilise information obtained in trypanosomes to study Leishmania. Overall, we expect one outcome from this study to be a greatly improved understanding on the roles of these biological processes in Leishmania, and the molecular mechanisms of the processes themselves - which will be relevant to many areas of biology. Another expected outcome will be knowledge on which peptidases are valid drug targets and this information will be exploited by collaborating with chemists to make inhibitors of peptidases, which might be used in the development of new drugs.

利什曼病是一种严重的人类疾病，也是世界上最被忽视的疾病之一，主要影响发展中国家的穷人。3.5亿人面临感染这种疾病的风险，它在健康和经济方面都付出了沉重的代价，并消耗了本可用于促进发展中国家增长的资源。目前还没有有效的疫苗来对抗这种疾病，化疗是减少利什曼病负担的主要手段。不幸的是，现有的药物有许多局限性，迫切需要新的药物。我们在这项工作计划中的目标是研究导致利什曼病的寄生虫利什曼原虫的关键生物过程，从而确定和验证潜在的药物靶点。我们已经表明，肽酶，消化蛋白质的酶，在利什曼原虫的发展中发挥核心作用，并在寄生虫的感染性和致病性中发挥重要作用。我们的工作将集中在寄生虫生物学的3个关键领域。首先，我们将确定对疾病的发病机制很重要的肽酶，并研究参与肽酶功能的关键途径。特别是，我们将调查一个过程称为自噬（自食），导致感染性寄生虫的发展，并允许寄生虫生活在哺乳动物宿主。我们还将研究寄生虫特异性肽酶，metacaspase的功能，这是必不可少的寄生虫的生长，但其功能尚不清楚。一个关键的方法将是对重要的利什曼原虫基因进行遗传操作，以找出编码的蛋白质在寄生虫的感染性和毒力中发挥的作用，并确定它们是否可以作为药物靶点。为了实现这一目标，我们将开发新的方法和研究工具，用于利什曼原虫的遗传操作。其次，我们将研究不同品系和不同种利什曼原虫的基因组变异。我们将对从苏丹患者身上分离出的利什曼原虫进行基因组测序，并确定影响疾病结果的基因。最后，我们将使用一个密切相关的寄生虫，非洲锥虫，作为研究肽酶功能的调节模型。非洲锥虫适合大规模研究，因此我们可以利用锥虫中获得的信息来研究利什曼原虫。总的来说，我们期望这项研究的一个结果是大大提高对利什曼原虫这些生物过程的作用以及这些过程本身的分子机制的理解-这将与生物学的许多领域相关。另一个预期的成果将是了解哪些肽酶是有效的药物靶点，这些信息将通过与化学家合作来利用，以制造可能用于新药开发的肽酶抑制剂。

项目成果

PNT1 Is a C11 Cysteine Peptidase Essential for Replication of the Trypanosome Kinetoplast.

• DOI: 10.1074/jbc.m116.714972
• 发表时间: 2016-04-29
• 期刊: The Journal of biological chemistry
• 作者: Grewal JS;McLuskey K;Das D;Myburgh E;Wilkes J;Brown E;Lemgruber L;Gould MK;Burchmore RJ;Coombs GH;Schnaufer A;Mottram JC
• 通讯作者: Mottram JC

Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex.

• DOI: 10.1371/journal.ppat.1008784
• 发表时间: 2020-10
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Burge RJ;Damianou A;Wilkinson AJ;Rodenko B;Mottram JC
• 通讯作者: Mottram JC

Conditional gene deletion with DiCre demonstrates an essential role for CRK3 in Leishmania mexicana cell cycle regulation.

• DOI: 10.1111/mmi.13375
• 发表时间: 2016-06
• 期刊: Molecular microbiology
• 影响因子: 3.6
• 作者: Duncan SM;Myburgh E;Philipon C;Brown E;Meissner M;Brewer J;Mottram JC
• 通讯作者: Mottram JC

Cysteine Peptidase B Regulates Leishmania mexicana Virulence through the Modulation of GP63 Expression.

• DOI: 10.1371/journal.ppat.1005658
• 发表时间: 2016-05
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Casgrain PA;Martel C;McMaster WR;Mottram JC;Olivier M;Descoteaux A
• 通讯作者: Descoteaux A

Inhibitor of serine peptidase 2 enhances Leishmania major survival in the skin through control of monocytes and monocyte-derived cells.

• DOI: 10.1096/fj.201700797r
• 发表时间: 2018-03
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Goundry A;Romano A;Lima APCA;Mottram JC;Myburgh E
• 通讯作者: Myburgh E