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

Reference	BB/W005867/1
Principal Investigator / Supervisor	Dr Catarina Gadelha
Co-Investigators / Co-Supervisors	Dr Bill Wickstead
Institution	University of Nottingham
Department	School of Life Sciences
Funding type	Research
Value (£)	534,459
Status	Current
Type	Research Grant
Start date	08/08/2022
End date	30/09/2025
Duration	38 months

Abstract

Animal African trypanosomiasis (AAT) is a substantial burden to agriculture in some of the poorest areas of the world. There is no vaccine against AAT, although recent work has shown great promise that one could be developed. In addition, diagnostic tools and drugs are limited, and there is growing resistance to veterinary trypanocides. Developments in these areas - including efficient use of the existing pipelines for vaccinology - are greatly hindered by lack of knowledge on the composition, variation and function of the cell surface for most AAT species. African trypanosomes are extracellular parasites of the blood and make use of extensive antigenic variation of surface proteins. However, the surface also supports essential cellular functions, and our previous work on cultured forms of Trypanosoma brucei has shown that many proteins not part of the major variable families are also present at the cell surface. Knowing the composition of the invariant component of the surface for other AAT species, and also the degree of variation in composition both between and within AAT species, are essential prerequisites for priming vaccinology pipelines or development of new diagnostics and antibody-based drug delivery. Here we will apply our validated approach using surface fluoresceination and semi-quantitative proteomics to define cell surface proteomes ('surfeomes') for animal-derived bloodstream-form parasites for the 3 most important AAT species: T. congolense, T. vivax and T. brucei. We will compare these surfeomes bioinformatically, identifying proteins and epitopes that are species-specific, those that are shared between the surfeomes, and also conserved homologues that have changed cellular location. Shared components will be used to functionally analyse the surfaces of the species. We will then use a fully quantitative method to test the variation in surfeome composition and protein abundance within an individual species.

Summary

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.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Animal Health, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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