Using the immune system's trojan horse for vaccination (360G-Wellcome-100954_Z_13_A)

Viral infections trigger an immune response characterized by induction of type I interferons (IFNs) that mediate many aspects of the host defence programme. Nucleic acids are often a molecular signature of infection and are detected by germline-encoded receptors that induce IFN expression. These innate sensors survey different subcellular compartments. We propose to study the detection of DNA in the cytosol, which is important not only during many bacterial and viral infections, but also in auto immune and autoinflammatory diseases and in DNA vaccination. However, the IFN inducing signalling pathways and the particular DNA sensors triggered by cytosolic DNA remain unknown or incompletely understood. The project includes four inter-related aims that individually and collectively ensure success. Firstly, we will study Aicardi-Gouti res syndrome (AGS), a monogenic autoinflammatory disease and model for other interferonopathies. We hypothesize that reverse transcribed cDNA from endogenous retroviruses triggers cytosolic DNA sensors in AGS. Secondly, we wish to identify cytosolic DNA sensing pathways detecting exogenous retroviruses such as HIV-1. Thirdly, we will establish the DNA virus Varicella zoster virus as a model to identify molecular players in cytosolic DNA sensing. Lastly, we will investigate the contribution of RNA polymerase III and RIG-I to DNA sensing. These projects constitute an integrated programme that will (i) identify cytosolic DNA sensors and pathways, (ii) establish new models, and (iii) define the role of cytosolic DNA sensing during infection with clinically relevant viruses and in autoinflammation. These ground-breaking studies will have potential impact on infectious disease, autoimmunity, DNA vaccination, and vaccine adjuvants.