MRC DiMeN Doctoral Training Partnership: Dissecting diversity of complement-binding cell surface proteins to enhance leptospiral vaccine efficacy

Description

Making vaccines more broadly protective and easily accessible can only increase uptake, decreasing both global antibiotic use and antimicrobial resistance (AMR). This is especially important for leptospirosis, a severe infectious disease of humans and animals which is emerging/re-emerging globally driven by global warming associated increases in extreme climatic events such as flooding.

Here, we combine synthetic biology, artificial intelligence (AI) and in silico approaches to investigate host specificity and guide engineering of bacterial surface proteins to develop a novel thermostable vaccine with broad Leptospira specificity and enhanced efficacy.

Specifically, this studentship will focus on dissecting mechanisms of host specificity by studying the molecular diversity of complement component 8 (C8)-binding surface proteins of leptospire bacteria in combination with functional (biochemical), immunological and AI-based analyses. These data will subsequently enable generation of bacterial surface proteins no longer able to bind C8 together with enhanced thermostability at both physiological and cold chain relevant temperatures. Such engineering means when the bacterial protein is used as a vaccine it will mitigate a key bacterial immune evasion mechanism which together with increased stability should enhance vaccine efficacy and accessibility. Development of such designer vaccines should underpin better worldwide control of leptospirosis.

The supervisors (Evans, Rigden, Crosby-Durrani) are in a strong position to offer substantial support to the successful candidate due to expertise in reverse vaccinology approaches, AI structural modelling and ability to culture fastidious spirochetes. This PhD studentship, is based in the Department of Infection Biology and Microbiomes and collaborates with computational biologists (with AI and protein structure expertise) from UoL Institute of Systems, Molecular and Integrative Biology to ensure a successful outcome.

This is a highly interdisciplinary project that sits at the interface between biochemistry, molecular microbiology and vaccinology. You will be primarily based at University of Liverpool Leahurst campus, with some work undertaken at the University of Liverpool city centre campus. The student will be able to attend University and DiMeN DTP-run courses in relevant topics and interact with postdoctoral and postgraduate researchers from a range of scientific backgrounds. Substantial training will be provided during the project enabling the student to gain a wide range of core and translational skills that should strategically enable development for a career in a range of different sectors. Training from primary supervisor will include microbiology, zoonoses, molecular biology/bacteriology, protein engineering, infection and global health, comparative genomics, biochemistry, immunology and reverse vaccinology. Second supervisor will allow for training in quantitative skills including large data, and in silico and AI approaches for protein structures. The additional secondary supervisor will provide training in statistics and histopathological techniques for spirochetes.

Applicants should have an upper second or first class degree in a relevant subject plus additional experience (e.g. Master’s degree or relevant employment). Please get in touch by email if you have questions about this project: pre-application enquiries are encouraged (please email Prof. Nicholas Evans: evansnj@liverpool.ac.uk). To apply please use the DiMeN DTP instructions below.

For more supervisor info, visit:

https://www.liverpool.ac.uk/people/nicholas-evans (primary supervisor)

https://www.liverpool.ac.uk/people/daniel-rigden (second supervisor)

https://www.liverpool.ac.uk/people/hayley-crosby-durrani (second supervisor)

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/