Taming the beast: Understanding the mechanisms that lead to attenuation of Theileria parasites.

Project Description for Find-A-PhD Advert (max 400 words). This will be the text that will be advertised to prospective students.

Theileria parva and Theileria annulata are tick-borne intracellular parasites that cause diseases of significant economic impact in a number of livestock species (including cattle, sheep and buffalo) in large areas of Europe, Africa and Asia. A key feature of these parasites is their ability to induce a 'tumour-like' phenotype in the host leukocyte cells they infect. As a consequence, infected cells are driven into rapid proliferation, leading to the pathology associated with infection.

Animals that are infected by administration of Theileria-infected cells generated by in vitro infection can suffer severe clinical disease if the in vitro cells have only been passaged for a short period of time (under 1 week). However, if the Theileria-infected cells are maintained for prolonged periods in vitro (>3 months) they become attenuated, and when administered to animals generate protective immunity whilst inducing only mild or no-clinical symptoms.

The ability of attenuated T. annulata-infected cells to induce immunity has been exploited to develop vaccines that are used in a number of countries in Asia and North Africa. Additionally, the ability of Theileria parasite to induce a reversible 'tumour-like' phenotype has been used as a model to understand the process of cancer-like transformation.

At present there is very limited high-resolution data available on the molecular mechanisms underlying the attenuation process in either Theileria parva or annulata-infected cells. We have recently generated a preliminary dataset looking at the changes of the transcriptome of T. parva-infected CD4+ T-cells as they transition from a pathogenic to an attenuated phenotype.

These data suggested roles for mitigation of host anti-inflammatory and proliferation pathways in the attenuation process, and identified a limited number of differentially expressed T. parva genes.

This project will exploit transcriptomics to conduct a series of analyses where Theileria-infected cells exhibiting disparate phenotypes (e.g. infected B-cells versus T-cells, infected cells from animals showing resistance or susceptibility to Theileria-induced disease in vivo) are compared in order to further explore the drivers of pathogenicity/attenuation. The successful candidate will be encouraged to undertake subsequent experiments using a range of techniques to validate the role of identified candidate genes in modifying the phenotype of Theileria-infected cells by assessing cellular/molecular parameters associated with attenuation/pathogenicity (e.g. proliferation, inflammatory stimulus) and the use of gene editing technologies (e.g.

CRISPR editing) to revert phenotypes. The supervisory team brings together expertise in immunology, parasitology, bioinformatics and host-pathogen biology and provides opportunities for training in a broad range of computational, in vitro and molecular biological skills.