The innate immune system provides an immediate response to infection and injury. It relies on the detection of pathogen-associated molecular patterns (PAMPs), molecular hallmarks of infection which are shared amongst different pathogens but are absent from healthy host cells. The detection of intracellular DNA as PAMP has emerged a key event in the innate immune response to DNA viruses, retroviruses and intracellular bacteria. In some circumstances the body’s own DNA can also be also detected as a danger-associated molecular pattern (DAMP), e.g. when DNA from dying cells is not cleared effectively, and this can play a role in the development of autoimmune conditions such as systemic lupus erythematosus.
One of the responses to foreign DNA is the secretion of interferons and pro-inflammatory cytokines, which then help to establish an antiviral state in the infected cell and its neighbours, and alert more specialised immune cells to the danger. Several proteins have been proposed to act as interferon-inducing DNA receptors, including most recently the enzyme cyclic GMP-AMP synthase, which provides a particularly elegant signalling pathway through production of cyclic GMP-AMP as second messenger. However, it is no yet know whether other receptor proteins also utilise this signalling pathway, how signalling is regulated, and how foreign DNA is distinguished from the cell's own genome.
The objectives of this project are:
1.) To test the involvement of DNA receptors in the recognition of DNA as 'stranger' and 'danger' signal in human cells
2.) To examine the interplay between DNA receptor candidates
3.) To identify novel regulators of the DNA-induced signalling pathway
4.) To define the nature of the DNA ligand that is recognised by innate immune receptors
By elucidating the molecular mechanisms of DNA sensing by the innate immune system, this project has great scientific and medical relevance for the fields of infection, vaccination and autoimmunity.
Fields of science
- medical and health scienceshealth sciencespublic and environmental healthepidemics preventionimmunisation
- natural sciencesbiological sciencesgenetics and hereditydna
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health scienceshealth sciencesinfectious diseaseDNA virus
- medical and health sciencesbasic medicineimmunology
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