Viruses are the smallest lifeform on earth and in order to replicate they need to deliver their genetic material under the form of nucleic acid, RNA or DNA, inside the host cell. Our immune system exploits this by using sensors which specifically recognize viral nucleic acids. However, our cells are packed with RNA and DNA molecules and how these sensors tell the difference between our own nucleic acid and that of a virus is a key question. Textbook biology learns that double-stranded RNA typically forms a helix. The host lab of dr. Jonathan Maelfait has found, however, that when a cell is infected with a virus, RNA adopts a zigzag or Z-conformation. We call this structure Z-RNA. Z-RNA acts as antiviral stimulant of antiviral immunity by activating the nucleic acid sensor ZBP1. Viral stimulation of ZBP1 instructs the cell to commit suicide. Killing of the infected cell is a very efficient mechanism to prevent viral spread. In this research proposal I wish to investigate the molecular signalling components that are required to induce antiviral cell death upon ZBP1 activation. Furthermore, I wish to characterize the Z-RNA molecules that originate during infection with important human pathogens such as Herpes simplex virus, Influenza A virus and Varicella zoster virus. Understanding the molecular pathways that regulate Z-RNA formation may help us to develop novel antivirals and vaccines.