Final Activity Report Summary - VIRAL IMMUNE EVASION (Using viral inhibitors to characterise signalling pathways involved in interferon induction) The innate immune system provides an immediate response to infections, when a cell is exposed to pathogen-associated molecular patterns (PAMPS), such as viral or bacterial DNA, RNA or proteins. The innate immune response to viruses involves the production of interferon-beta, which is secreted from infected cells with the aim of establishing an 'antiviral state' within the cell, and of alerting neighbouring cells to the danger. Viruses, in turn, having co-evolved with their host, possess means to evade and inhibit the interferon response, which allows them to establish a productive infection.Vaccinia virus, a poxvirus with more than 200 genes, has a particularly large repertoire of tools to inhibit the host immune system. With the aim of finding new vaccinia virus proteins that inhibit the innate immune system, we screened 49 previously uncharacterised vaccinia virus proteins for inhibition of the interferon response in cultured human cells. Five of the 49 proteins tested had a strong inhibitory effect, blocking the expression of an interferon-beta reporter gene when the cells were exposed to cytoplasmic double-stranded RNA or DNA, which are hallmarks of viral infection. We have characterised these viral proteins in more detail, and have identified which cellular signalling pathways they inhibit. We are currently searching for host proteins that are targeted by the inhibitors. In this way, the vaccinia virus proteins that we identified may help us to understand the workings of the innate immune system. Also, the viral inhibitors could be useful for the design of therapeutics aimed at blocking excessive inflammation, for instance in arthritis and septic shock.
