MRC DiMeN Doctoral Training Partnership: Understanding the mechanisms of norovirus replication

Since the introduction of the rotavirus vaccine, norovirus is the dominant cause of viral gastroenteritis worldwide. Globally it causes ~685 million cases/year, including >50,000 deaths in the infant and elderly populations (CDC, 2024). In the UK, norovirus cases have recently reached a five-year high over pre-pandemic levels, primarily associated with health and social care settings (UKHSA). In 2018, direct and indirect costs to the NHS alone were estimated as £297M annually (Sandmann et al. 2018), and the overall cost of norovirus to the economy was estimated by the FSA as £1,68B/year. The “winter vomiting bug” as it is colloquially known, makes headlines every year, despite this there is no licensed antiviral or vaccine to treat norovirus infections, and treatments are supportive (i.e. rehydration).

Effective antivirals usually target one or more steps of viral replication, therefore to develop effective antivirals against norovirus, we need a greater understanding of the process of norovirus replication. Viral enzymes are the logical focus as these are not present in uninfected cells. During norovirus replication viral enzymes are cleaved from a single long polyprotein and have distinct functions in both fully and partially-cleaved states. We seek to identify which states correspond to distinct roles of these enzymes during viral infection to develop these as drug targets.

Objectives

1.     Analyse norovirus polyprotein cleavage product dynamics and abundance throughout infection by mass spectrometry

2.     Assess the roles of individual cleavage events using long-read sequencing, viral reverse genetics, and biochemical characterisation.

Experimental approach

This project incorporates multidisciplinary training in molecular virology, biochemistry, mass spectrometry-based proteomics, transcriptomics and bioinformatics (e.g. R/Matlab). The primary model used will be murine norovirus which is extensively studied in the Emmott lab and grows efficiently in cell culture.

Supervisory team

In this PhD, you will receive training in molecular virology, mass spectrometry-based proteomics, data analysis in R/Matlab, and nanopore-based long-read sequencing. You will be based in Dr Ed Emmott’s lab (https://emmottlab.org/, https://www.liverpool.ac.uk/people/edward-emmott) at the Centre for Proteome Research, University of Liverpool which has research programmes on norovirus and coronavirus biology, as well as proteomics methods development. This studentship complements a large Wellcome-funded project to study coronavirus polyprotein dynamics and it shares the majority of approaches with this project. The second supervisor Dr Dominic Bryne (https://www.liverpool.ac.uk/people/dom-byrne) is an experienced biochemist, and will support with protein expression and in vitro assays, and Prof. Al Darby (https://www.liverpool.ac.uk/people/alistair-darby) will support on RNAseq design and analysis. In the first instance, please address any questions to Dr Ed Emmott, at e.emmott@liverpool.ac.uk

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/