Metabolism and drug resistance probed with new genetic tools in the neglected animal pathogen Trypanosoma vivax.

用新的遗传工具探讨了被忽视的动物病原体间日锥虫的代谢和耐药性。

• 批准号: BB/W000296/1
• 负责人: Liam Morrison
• 金额: $ 52.79万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW000296%2F1
• 关键词: Metabolism; drug; resistance; probed; new

Animal African Trypanosomiasis (AAT) is a debilitating disease of cattle and other livestock, caused mainly by two species of single-celled parasite: Trypanosoma congolense and Trypanosoma vivax. There are ~70 million cases of AAT each year, causing ~3 million deaths and creating a great economic burden on rural communities. As well as causing disease in Africa, T. vivax has also spread to South America, where it is an increasing problem. Despite being a globally important pathogen, T. vivax is severely neglected in terms of knowledge and research effort - due largely to the lack of good systems in place for maintaining the parasite outside of animals or for investigating the function of its individual genes. T. vivax is genetically distinct from better-studied trypanosomes, with around one third of all T. vivax genes not being found in related species - this is mirrored in important differences in the biology of the parasite, including its transmission through the insect vector, evasion of the host immune system, and its resistance to drugs. Advancement of both fundamental knowledge and laboratory capabilities are needed to transform the ability to work meaningfully with T. vivax , and to design tools to consequently reduce the impact of AAT. This project will do both; by generating new knowledge on key areas of T. vivax biology and developing a toolkit for culturing and genetic transformation of the parasite.We will characterise the core metabolism of T. vivax by analysing the pattern of gene expression and what chemicals the parasites use/produce. This will enable us to define the chemical processes going on inside T. vivax cells, and we will test these predictions with targeted chemical inhibitors and interfering with expression of specific genes. We will also characterise the proteins on the surface of T. vivax, which are the parts of the cell in direct contact with the host, including those responsible for key metabolite and drug uptake. We will generate parasites resistant to three drugs (the two drugs currently widely used in the field, and one in clinical development) and identify genetic changes responsible for resistance. By comparing these to information on T. vivax metabolism, surface composition, and data from functional studies in other trypanosomes, we will decode mechanisms of drug resistance in T. vivax for the first time. Finally, we aim to develop critical laboratory resources for T. vivax. Information on parasite metabolism and surface complement will be used to design chemical formulations that will support growth of T. vivax outside of animals, as has been done for other trypanosomes. We will also develop a genetic toolkit for T. vivax to enable functional analysis of its genes, which will feed directly into our aims of understanding of metabolism and drug resistance. The project will build upon relevant expertise of the team, who have experience in successfully tackling similar questions for the related parasites T. brucei and T. congolense, and complements the drug development efforts of our industrial partner, the Global Alliance for Livestock Veterinary Medicines (GALVmed). The outputs will be particularly relevant to drug development and drug sustainability - understanding drug resistance to existing and new drugs enables informed design of drug usage that can maximise the lifetime of treatments. Additionally, advancing our knowledge of core metabolism has the potential to identify novel drug targets, and the ability to culture T. vivax would enable the scaling up of drug discovery efforts. Therefore, achieving these aims will transform our ability to work with T. vivax, generating foundational knowledge and datasets, and advancing fundamental and applied research capabilities for this significantly neglected pathogen.

非洲锥虫病（英语：Animal African Trypanosomaly，AAT）是一种危害牛和其他牲畜的疾病，主要由两种单细胞寄生虫引起：刚果锥虫和间日锥虫。每年约有7000万例AAT病例，造成约300万人死亡，并给农村社区造成巨大的经济负担。T.间日疟原虫也已传播到南美洲，在那里它是一个日益严重的问题。尽管T.间日疟原虫在知识和研究工作方面受到严重忽视，主要是由于缺乏良好的系统来维持动物体外的寄生虫或研究其单个基因的功能。T.间日疟原虫在遗传学上与更好地研究的锥虫不同，大约三分之一的锥虫。间日疟原虫的基因在相关物种中没有发现----这反映在寄生虫生物学的重要差异上，包括通过昆虫媒介传播，逃避宿主免疫系统，以及对药物的抗药性。基础知识和实验室能力的进步是需要转变的能力，有意义地与T。间日疟原虫，并设计工具，从而减少AAT的影响。这个项目将做到这两点，通过产生新的知识的关键领域的T。间日疟原虫生物学的研究，并开发了一套用于培养和遗传转化间日疟原虫的工具。通过分析基因表达模式和寄生虫使用/产生的化学物质来研究间日疟原虫。这将使我们能够定义T细胞内部发生的化学过程。间日疟原虫细胞，我们将测试这些预测与有针对性的化学抑制剂和干扰特定基因的表达。我们还将对T.间日疟原虫，它们是细胞中与宿主直接接触的部分，包括负责关键代谢物和药物摄取的部分。我们将产生对三种药物（目前在该领域广泛使用的两种药物，以及临床开发中的一种药物）具有抗性的寄生虫，并确定导致抗性的遗传变化。通过与T.间日疟原虫代谢，表面组成和其他锥虫的功能研究数据，我们将解码T.间日疟原虫首次出现最后，我们的目标是为T。间日疟原虫寄生虫代谢和表面补体的信息将被用来设计化学制剂，将支持T。动物体外的间日疟原虫，就像对其他锥虫所做的那样。我们还将开发T.间日疟原虫，使其基因的功能分析，这将直接饲料到我们的目标，了解代谢和耐药性。该项目将建立在团队的相关专业知识基础上，他们有成功解决相关寄生虫T。brucei和T.我们的合作伙伴是全球畜牧兽医药物联盟（GALVmed）。这些产出将与药物开发和药物可持续性特别相关-了解对现有药物和新药物的耐药性，可以使药物使用的知情设计能够最大限度地延长治疗寿命。此外，推进我们的核心代谢知识有可能确定新的药物靶点，并培养T。间日疟原虫将使药物发现工作得以扩大。因此，实现这些目标将改变我们与T。间日疟原虫，产生基础知识和数据集，并推进这一被严重忽视的病原体的基础和应用研究能力。

项目成果

Pathogenicity and virulence of African trypanosomes: From laboratory models to clinically relevant hosts.

• DOI: 10.1080/21505594.2022.2150445
• 发表时间: 2023-12
• 期刊: Virulence
• 影响因子: 5.2

Anti-parasitic benzoxaboroles are ineffective against Theileria parva in vitro.

• DOI: 10.1016/j.ijpddr.2023.10.003
• 发表时间: 2023-12
• 期刊: INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
• 影响因子: 4
• 作者: Steketee, Pieter C.;Paxton, Edith;Barrett, Michael P.;Pearce, Michael C.;Connelley, Timothy K.;Morrison, Liam J.
• 通讯作者: Morrison, Liam J.