MRC DiMeN Doctoral Training Partnership: How interferon defends the brain against viral invasion

Contrary to the perception of the brain as an ‘immune-privileged’ organ, it is now clear that the brain engages a potent immune signalling network to defend itself against viral infection (encephalitis). Antiviral cytokines known as type I interferons (IFN alpha/beta) appear central to this response.

We have recently shown that IFN alpha/beta is essential for antiviral immunity in humans (1), consistent with data from model organisms. This is exciting because it suggests that the interferon pathway could be a potential therapeutic target in encephalitis – a serious viral disease and an area of major unmet medical need.

These findings also highlight important areas of uncertainty, such as which brain cell-types make IFN alpha/beta, what effector functions are triggered by IFN alpha/beta in these cell types, and how this response is calibrated to prevent damaging immunopathology. We now have the tools to address these questions, through the recent development of induced pluripotent stem (iPS) cell models of key human brain cells (2) including microglia– brain-resident immune cells – and cortical neurones, the main target of neurotropic viruses.

This project focuses on two globally-important neurotropic viruses: herpes simplex virus 1 (HSV1) - the most common cause of sporadic viral encephalitis - and Zika virus (ZIKV) - an emerging cause of congenital encephalitis. Our preliminary data reveal intriguing differences in the IFN alpha/beta response of microglia and neurones which impact antiviral defence.

Techniques:
You will characterise HSV1 and ZIKV replication in patient-derived iPS models of brain cells carrying genetic lesions of type I IFN signalling (1, 3). In parallel you will introduce relevant mutations into control iPS cells using CRISPR/Cas9. Finally, you will apply a range of techniques to profile gene promoter and enhancer activity (ChIP-seq), expression (RNAseq) and chromatin accessibility (ATACseq) in neural progenitor cells, cortical neurones and microglia, providing a comprehensive map of cell-type specific regulation of the IFN alpha/ beta response.

You will emerge with a unique skillset - combining cutting-edge techniques in bench and computational analysis - relevant to a broad range of biomedical disciplines. The multidisciplinary supervisory team, which supports two current MRC DiMeN students, provides training in both viral immunology and computational genomics, complemented by expertise in genome editing accessible through a training attachment to the James Martin Stem Cell Facility (Oxford University).

Impact:
This project will help to unravel the cell types and cell-cell signalling events that coordinate the interferon network in the human brain, shedding new light on the role of this fundamental pathway in control of important viral pathogens. Furthermore, the results could open up new therapeutic opportunities by providing proof-of-concept for strategies designed to leverage this potent antiviral response.

Supervisory expertise:
Viral immunology - Dr Christopher Duncan (https://www.ncl.ac.uk/icm/people/profile/christopherduncan.html#research)
Computational genomics – Dr Daniel Rico (https://www.ncl.ac.uk/icm/people/profile/danielrico.html#background)
Inborn errors of immunity – Prof Sophie Hambleton (https://www.ncl.ac.uk/icm/people/profile/sophiehambleton.html#background)
Microglia and genome editing – Prof William James (https://www.path.ox.ac.uk/content/william-james)

Informal enquires are encouraged: [Email Address Removed]


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 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, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/