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Priming vaccinology for livestock trypanosomes: definition and diversity of the cell surface landscape

家畜锥虫的启动疫苗学：细胞表面景观的定义和多样性

基本信息

批准号：
BB/W005867/1
负责人：
Catarina Gadelha
金额：
$ 68.1万
依托单位：
University of Nottingham
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%2FW005867%2F1
关键词：
Priming vaccinology livestock trypanosomes definition

项目摘要

African trypanosomes are single-celled parasites of the blood that cause devastating diseases of livestock in Africa, and have also spread to parts of South America and Asia. These parasites are a substantial threat to food security and impose a major burden on meat and dairy production in some of the poorest areas of the world (for example, the livestock disease nagana kills ~3 million cattle per year and creates an estimated loss of ~$4 billion from African economies). There is currently no vaccine against these parasites, diagnostic tools are limited, and increasing drug resistance makes the need for new drugs or new methods to deliver existing drugs urgent. Understanding the cell surface is critical to the challenges above: the surface is the site of binding for antibody-based drug delivery, it contains proteins that could distinguish between different types of trypanosome infection, and changes to surface biology are a means for the emergence of drug resistance. Moreover, recent work has shown protective immunity against African trypanosomes based on surface molecules, strongly suggesting that an effective vaccine against these parasites could be found by screening invariant surface proteins. However, research in these areas is greatly hindered by lack of information on the proteins that make up the surface in the African trypanosome species that cause the greatest burden of livestock disease. In addition, we are currently unable to compare the surfaces for different trypanosome species to understand how the surface functions, or what parts of the surface are highly variable or constrained by function (and hence cannot change). We have previously developed methods for robust isolation and validation of cell surface components for a laboratory strain of African trypanosomes used as a model for human disease. Here, we will use these methods to define the proteins found at the surface of the 3 species of African trypanosomes that are most important for livestock disease. Using parasites taken from animal disease models, we will compare the parasite surfaces in terms of composition (which proteins are present) and also sequence (which parts of the proteins change) in order to identify shared components that are likely constrained by function and common to the different species. We will use these shared components, in combination with tools we and others have developed for genetic modification of livestock trypanosome species, to understand how the surfaces of the species differ and test for protein accessibility to the immune system. Finally, we will use a method that can identify proteins and also accurately measure their abundance to test for the degree of variation in the surface that occurs in an individual species. These data will show how quickly the surface of these important parasites changes - both within a species and over longer periods. It will also identify shared invariant components of the surface that are potential targets for vaccines and drug delivery, and begin to functionally understand the surfaces of the different parasites.

非洲锥虫是血液中的单细胞寄生虫，在非洲引起牲畜的毁灭性疾病，并已蔓延到南美洲和亚洲的部分地区。这些寄生虫对粮食安全构成重大威胁，并对世界上一些最贫穷地区的肉类和乳制品生产造成重大负担（例如，牲畜疾病nagana每年导致约300万头牛死亡，并给非洲经济造成约40亿美元的损失）。目前没有针对这些寄生虫的疫苗，诊断工具有限，而且不断增加的耐药性使得迫切需要新药或提供现有药物的新方法。了解细胞表面对于上述挑战至关重要：表面是基于抗体的药物递送的结合位点，它含有可以区分不同类型锥虫感染的蛋白质，表面生物学的变化是出现耐药性的一种手段。此外，最近的工作表明，对非洲锥虫的保护性免疫基于表面分子，这强烈表明，可以通过筛选不变的表面蛋白找到针对这些寄生虫的有效疫苗。然而，由于缺乏关于构成非洲锥虫物种表面的蛋白质的信息，这些领域的研究受到很大阻碍，而这些物种是造成牲畜疾病最大负担的。此外，我们目前还无法比较不同锥虫物种的表面，以了解表面的功能，或者表面的哪些部分是高度可变的或受功能限制的（因此不能改变）。我们以前已经开发了用于作为人类疾病模型的非洲锥虫实验室菌株的稳健分离和细胞表面组分验证的方法。在这里，我们将使用这些方法来确定在3种非洲锥虫表面发现的蛋白质，这3种锥虫对牲畜疾病最重要。使用从动物疾病模型中提取的寄生虫，我们将比较寄生虫表面的组成（存在哪些蛋白质）和序列（蛋白质的哪些部分发生变化），以确定可能受功能限制且不同物种共有的共同成分。我们将利用这些共享的成分，结合我们和其他人为家畜锥虫物种的基因改造开发的工具，了解物种表面的差异，并测试免疫系统的蛋白质可及性。最后，我们将使用一种可以识别蛋白质并准确测量其丰度的方法来测试单个物种表面变化的程度。这些数据将显示这些重要寄生虫的表面变化有多快——无论是在一个物种内还是在更长的时间内。它还将确定表面的共同不变成分，这些成分是疫苗和药物递送的潜在目标，并开始从功能上了解不同寄生虫的表面。