Variant antigen profiling: a novel genomic tool for diagnosis and surveillance of animal African trypanosomiasis.

变异抗原分析：一种用于诊断和监测非洲动物锥虫病的新型基因组工具。

• 批准号: BB/M022811/1
• 负责人: Andrew Jackson
• 金额: $ 59.28万
• 依托单位: University of Liverpool
• 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=BB%2FM022811%2F1
• 关键词: Variant; antigen; profiling; novel; genomic

Animal African trypanosomiasis (AAT) is a livestock disease with frequent and devastating effects on animal health and on the development of sub-Saharan nations. This neglected tropical disease is caused by the parasite Trypanosoma congolense, which is spread by biting flies and infects the blood causing chronic anaemia, wastage and ultimately death if untreated. Unlike Human African trypanosomiasis ('sleeping sickness'), which is caused by a related parasite T. brucei, and is declining after successful intervention and much research, AAT remains very common and poorly known. Yet the annual costs of disease and treatment are estimated at ~$4.5 billion across 37 countries. The FAO considers AAT to "lie at the heart of Africa's struggle against poverty", and central to its Millennium Goals. Most research on African trypanosomes is directed at the model organism T. brucei, but given the profound effects of AAT on animals and people, we need research dedicated to the veterinary parasites to determine how parasite variation affects the course and severity of disease.All African trypanosomes use antigenic variation to avoid the immune response of their host. This involves the replacement of the protein coat covering the parasite surface each time the host produces antibodies to the protein. The protein is called the Variant Surface Glycoprotein (VSG) and is crucial to parasite survival and the severity of disease, determining the length of infection and resistance to innate host defences. The genomes of both T. brucei and T. congolense contain hundreds of VSG genes, of which just one is expressed at a time from a specific expression site. Together, this repertoire of alternative VSG genes is a ubiquitous, but highly variable, feature of trypanosome genomes that constantly changes in response to host immunity. We can use this repertoire to understand how parasites change through space and time, and what effect this has on disease. This project aims to measure variation in VSG repertoire across the T. congolense population, and then produce a novel tool for rapidly predicting the properties of a strain based on its VSG repertoire.I will produce genome sequences for 40 isolates sampled from T. congolense infections of cows. Until now, analysis of VSG repertoires on a population scale has been avoided because their complexity makes it impossible to use standard tools. Previously, I discovered that T. congolense VSG are divided into distinct types, each defined by unique protein motifs. I will quantify the VSG repertoire in each T. congolense isolate by comparing its VSG to these protein motifs. The relative abundance of the VSG types will produce a 'variant antigen profile' (VAP) for each isolate. To give the VAP some predictive power, I will identify which VSG are actually used in antigenic variation, (and those that might perform some other role), by identifying the active VSG gene present in the specific expression site and expressed on the parasite cell surface. I will also identify significant correlations of VAPs with geography, time, disease severity and parasite relatedness. A tool to generate and interpret a VAP will be accessible online, making it possible to predict the properties of any T. congolense isolate from genome sequence data using variant antigen profiling.AAT represents an enormous challenge to animal health and economic development in Africa and yet we have no detailed knowledge of how T. congolense varies and how this relates to the kind of disease we see. Such information would improve diagnosis, the efficiency of drug therapy and control measures, lead to earlier and more appropriate treatment for sick animals, and perhaps even identify proteins that could serve as vaccine targets. The time is right to develop a fast and simple approach to making sense of VSG diversity that can unlock the potential of trypanosome genomics for understanding AAT, estimating its risk and mitigating its effects.

非洲动物锥虫病 (AAT) 是一种牲畜疾病，对动物健康和撒哈拉以南国家的发展造成频繁且具有破坏性的影响。这种被忽视的热带疾病是由寄生虫刚果锥虫引起的，这种寄生虫通过叮咬苍蝇传播并感染血液，导致慢性贫血、浪费，如果不治疗，最终会导致死亡。非洲人类锥虫病（“昏睡病”）是由相关寄生虫布氏锥虫引起的，并且在成功干预和大量研究后正在下降，而 AAT 仍然非常常见且鲜为人知。然而，37 个国家每年的疾病和治疗费用估计约为 45 亿美元。粮农组织认为非洲农业技术“是非洲反贫困斗争的核心”，也是其千年目标的核心。大多数关于非洲锥虫的研究都是针对模型生物布氏锥虫，但考虑到 AAT 对动物和人类的深远影响，我们需要专门针对兽医寄生虫进行研究，以确定寄生虫变异如何影响疾病的病程和严重程度。所有非洲锥虫都利用抗原变异来避免宿主的免疫反应。这涉及每次宿主产生蛋白质抗体时更换覆盖寄生虫表面的蛋白质外壳。这种蛋白质被称为变异表面糖蛋白（VSG），对于寄生虫的生存和疾病的严重程度至关重要，决定感染的持续时间和对宿主先天防御的抵抗力。布氏锥虫和刚果锥虫的基因组均含有数百个 VSG 基因，其中每次仅从特定表达位点表达一个。总之，这些替代 VSG 基因是锥虫基因组普遍存在但高度可变的特征，它会随着宿主免疫而不断变化。我们可以利用这个库来了解寄生虫如何随空间和时间变化，以及这对疾病有何影响。该项目旨在测量刚果锥虫种群中 VSG 谱系的变异，然后开发一种新工具，用于根据其 VSG 谱系快速预测菌株的特性。我将为从牛的刚果锥虫感染中取样的 40 个分离株生成基因组序列。到目前为止，人们一直避免在人口规模上对 VSG 曲目进行分析，因为它们的复杂性使得无法使用标准工具。之前，我发现刚果锥虫 VSG 分为不同的类型，每种类型都由独特的蛋白质基序定义。我将通过将每个刚果锥体分离株的 VSG 与这些蛋白质基序进行比较来量化其 VSG 谱。 VSG 类型的相对丰度将为每个分离株产生“变异抗原谱”(VAP)。为了赋予 VAP 一些预测能力，我将通过识别特定表达位点中存在并在寄生虫细胞表面上表达的活性 VSG 基因来确定哪些 VSG 实际用于抗原变异（以及那些可能发挥其他作用的 VSG）。我还将确定 VAP 与地理位置、时间、疾病严重程度和寄生虫相关性的显着相关性。可以在线访问生成和解释 VAP 的工具，从而可以使用变异抗原分析从基因组序列数据中预测任何刚果锥虫分离株的特性。AAT 对非洲的动物健康和经济发展构成了巨大挑战，但我们对刚果锥虫如何变化以及这与我们所看到的疾病类型有何关系还没有详细的了解。这些信息将改善诊断、药物治疗和控制措施的效率，为患病动物提供更早、更适当的治疗，甚至可能确定可以作为疫苗靶标的蛋白质。现在正是开发一种快速、简单的方法来理解 VSG 多样性的时候，这种方法可以释放锥虫基因组学在理解 AAT、估计其风险和减轻其影响方面的潜力。

项目成果

Transcriptomic Profiling of Trypanosoma Congolense Mouthpart Parasites from Naturally Infected Flies

自然感染果蝇刚果锥虫口器寄生虫的转录组分析

• DOI: 10.21203/rs.3.rs-1292471/v1
• 发表时间: 2022
• 作者: Pereira S

MOESM8 of Clinical expression and antigenic profiles of a Plasmodium vivax vaccine candidate: merozoite surface protein 7 (PvMSP-7)

MOESM8 间日疟原虫候选疫苗的临床表达和抗原谱：裂殖子表面蛋白 7 (PvMSP-7)

• DOI: 10.6084/m9.figshare.8275583
• 发表时间: 2019
• 作者: Chew Cheng

MOESM5 of Clinical expression and antigenic profiles of a Plasmodium vivax vaccine candidate: merozoite surface protein 7 (PvMSP-7)

间日疟原虫候选疫苗的临床表达和抗原谱的 MOESM5：裂殖子表面蛋白 7 (PvMSP-7)

• DOI: 10.6084/m9.figshare.8275562
• 发表时间: 2019
• 作者: Chew Cheng

The Structure of a Conserved Telomeric Region Associated with Variant Antigen Loci in the Blood Parasite Trypanosoma congolense.

• DOI: 10.1093/gbe/evy186
• 发表时间: 2018-09-01
• 期刊: Genome biology and evolution
• 影响因子: 3.3
• 作者: Abbas AH;Silva Pereira S;D'Archivio S;Wickstead B;Morrison LJ;Hall N;Hertz-Fowler C;Darby AC;Jackson AP
• 通讯作者: Jackson AP

MOESM7 of Clinical expression and antigenic profiles of a Plasmodium vivax vaccine candidate: merozoite surface protein 7 (PvMSP-7)

MOESM7 间日疟原虫候选疫苗的临床表达和抗原谱：裂殖子表面蛋白 7 (PvMSP-7)

• DOI: 10.6084/m9.figshare.8275574
• 发表时间: 2019
• 作者: Chew Cheng