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

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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.