Trypanosomes are master of disguise:
African trypanosomes cause huge morbidity and economic burden amongst some of the world’s poorest populations. Like malaria parasites, trypanosomes can systematically alter the identity of proteins displayed to the host immune system - such antigenic variation has greatly challenged vaccine development against these organisms. Indeed, there is no vaccine currently available.
Key to successful antigenic variation is the ability to 1) express a single antigen at a time; 2) periodically switch the antigen coat through genetic and/or epigenetic mechanisms. Notably in trypanosomes, a set of proteins that form nuclear condensates and several nuclear bodies control this singular antigen expression and ensure that the active antigen is expressed at very high levels (Faria et al, 2019, PMID: 31289266; Faria et al, 2021, PMID: 33432154; Budzak et al, 2022, PMID: 35013170; Lopez-Escobar et al, PMID: 35879525).
We seek to investigate how the composition and spatial organisation of these bodies in the nucleus is affected when trypanosomes switch expression of one antigenic variant to another.
The experimental approaches will include:
- Development of genetic reporters for antigenic switching and visualisation of DNA loci for subsequent super resolution microscopy analysis.
- Study of condensate formation/ablation using cutting-edge imaging techniques (super-resolution, including 3D-SIM and STORM, ultra-structure expansion microscopy, FRAP).
- Highly temporally and spatially resolved proximity labelling approaches combined with quantitative low input mass spectrometry.
Impact & Novelty:
Notably, trypanosomes infect people and devastate livestock in central Africa (economic losses in the range of US$1.0-1.2 billion), new intervention strategies are desperately needed. One of the main obstacles to vaccine development has been their eximious ability to undergo antigenic variation. The machinery responsible for singular antigen expression out of thousands of possible genes remained elusive for decades but has recently been identified for the first time in any eukaryote, presenting an unprecedented opportunity to specifically target antigenic variation.
The supervisory team:
The supervisors have world-leading expertise in parasite genetics, gene expression regulation, and advanced imaging techniques. The primary supervisor is a new PI and is herself still in the lab therefore providing ‘hands-on’ training. The Faria (Twitter: @JoanaRCF), McCulloch (Twitter: @McCulloch_Group) labs and the Universities of York and Glasgow promote a positive and accepting research culture where people are free and welcome to be who they are. We seek a highly driven, motivated, creative, and dedicated individual.
The York Biomedical Research Institute at the University of York is committed to recruiting extraordinary future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation, religion/belief, marital status, pregnancy and maternity, or career pathway to date. We understand that commitment and excellence can be shown in many ways and have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.