How is intracellular DNA detected during infection?

DNA is usually confined to the nucleus of our cells. However, during cell damage or infection, DNA can be released into the cytosol and can be detected by the innate immune system. The DNA-induced innate immune response is important for the defence against viruses and other intracellular pathogens, and can also be utilised for therapeutic approaches, e.g. in the immunotherapy of cancer. On the other hand, over-activation of the DNA sensing response can cause autoinflammatory conditions or an acute cytokine storm resulting in tissue damage, if the response not appropriately regulated.
Double-stranded DNA in the cytosol is detected by the DNA sensor cGAS, which activates the adaptor protein STING. This ultimately results in the production of interferons, cytokines and chemokines for the activation of a local immune response. Several additional intracellular DNA sensors exist, which either work together with cGAS or activate alternative signalling cascades (Unterholzner, Immunobiology, 2013). The DNA binding protein IFI16 for instance co-operates with cGAS in the detection of viral DNA in the cytosol, but can also bind DNA in the nucleus and activate STING, when the cell’s own DNA is damaged (Almine et al., Nature Communications, 2017; Dunphy et al., Molecular Cell, 2018).
Still much is to be learnt about the interaction of different kinds of DNA with the DNA sensors in the host, and the regulation of the DNA sensing pathways during infectious disease and inflammation. In this project, you will investigate whether single-stranded or structured DNA molecules can be detected by DNA sensors in the cell, and whether this can prime, activate or inhibit the innate immune response during infections. You will use a range of molecular and cell biology techniques, including cell culture, infection assays, real-time PCR, ELISA, DNA pull-down assays, CRISPR gene editing and confocal microscopy. Findings from this project may help us understand how our cells detect DNA during infection and how this system could be modulated for clinical benefit.

We are looking for a highly motivated candidate with a strong background in molecular biology or immunology, and an interest in host-pathogen interactions. Requirements are a MSc or BSc qualification (2.i or higher) in a relevant field, excellent communication skills and some relevant laboratory experience. A previous laboratory placement in industry or academia would be advantageous. You will join a vibrant, friendly group in a supportive research environment at the Division of Biomedical and Life Sciences, Lancaster University.

This is a funded 3 year PhD studentship open to UK/EU applicants. The anticipated start date is January 2021.

To apply, please send a CV (2 pages), details of two academic references and a cover letter outlining your experience and interest in the studentship (max 2 pages) to Dr Leonie Unterholzner ([Email Address Removed]) by September 28th, 2020.