What is it about?
Eukaryotic cells normally store their DNA in the nucleus (and in mitochondria). The presence of DNA in aberrant locations, such as the cytoplasm, constitutes a pathogen-associated molecular pattern that triggers innate immune activation including interferon production. In contrast, the nucleus has long been considered an ‘immune-privileged’ site for DNA detection. Over the past few years, several intracellular foreign DNA sensors have been identified. Surprisingly, at least one major sensor of viral double-stranded DNA (a protein referred to as gamma-interferon-inducible protein 16 or IFI16) resides and functions predominantly in the nucleus. This observation and other findings challenge the view that location is the only factor determining foreign DNA sensing and imply mechanisms that distinguish between ‘self’ and ‘non-self’ DNA in the nucleus, the site of replication of most DNA viruses. Nuclear DNA usually exists as chromatin composed of nucleosomes (DNA wrapped around histone octamers). We have previously shown that the double-stranded DNA genome of cytomegalovirus (CMV), one of eight human herpesviruses, is chromatinized in a way that differs from the structure of typical cellular chromatin in terms of both nucleosome organisation and histone modifications. We propose that, rather than recognising viral nuclear DNA (which may be indistinguishable from cellular DNA), the cell may distinguish between viral and cellular chromatin structures to activate innate immune signalling from the nucleus.The PhD project will investigate how the structure of CMV chromatin, including nucleosome organisation and histone modifications, is linked to viral DNA sensing in the nucleus and how nuclear foreign DNA triggers innate immune signalling including interferon responses. The results from this multi-disciplinary project are expected to contribute significantly to our basic understanding of cellular responses to foreign DNA and of key innate immune events underlying the outcome of herpesvirus infection and pathogenesis. They may also break ground for new strategies of targeting CMV, a virus which remains a major cause of childhood disability and disease in immunosuppressed patients.
Where will it be?
St Andrews is a beautiful, very welcoming and highly cosmopolitan seaside town in the east of Scotland. The University of St Andrews, founded in 1413, is Scotland's first university and consistently ranked in the UK’s top five (3rd according to the Guardian University Guide 2017). St Andrews is also named UK University of the Year for teaching quality in The Times and Sunday Times University Guide 2017. In REF 2014, the impact of research undertaken in the Biological Sciences at St Andrews was rated 2nd across the UK, and 84% of research was judged world leading or internationally excellent. The Biomedical Sciences Research Centre (BSRC) is an interdisciplinary research centre spanning biology, chemistry, physics and medicine. Core facilities include imaging (confocal microscopy), proteomics, synthetic chemistry and bioinformatics. The ethos of the BSRC is to break down barriers between disciplines and conduct world class research focused on the broad theme of infection including molecular virology.
The student will receive training in a wide variety of cutting-edge molecular, cellular and computational techniques in virology, epigenetics and immunology. Training in these areas provides an excellent pool of skills and knowledge to be well positioned for a future research career in academia or industry. A comprehensive range of opportunities to support personal, professional and academic development through the Centre for Academic, Professional and Organisational Development (CAPOD) at the University of St Andrews will also be available. You will join a supportive and productive research group studying viruses relevant to human health in well-equipped laboratories.
How can I apply?
We invite online applications from highly committed students, preferentially with a background in molecular biology, cell biology, (epi)genetics, immunology or similar disciplines. The applicant should hold or expect at least a 2:1 Honours or similar degree from a UK or EU University. Funding will be provided by a School of Biology Postgraduate Scholarship. Externally funded students interested in this or similar projects are welcome to apply at any time, but should contact Dr Nevels first (contact details below).