Entry, innate sensing and replication of enteropathogenic caliciviruses. (360G-Wellcome-207498_Z_17_Z)

Our overarching aim is to gain insights into the biology of enteropathogenic caliciviruses, focusing on the fundamental aspects that have remained elusive to date: viral entry into target cells, the interplay with the host innate response and the recruitment of host-cell co-factors that support replication. Having significantly improved the culture systems for human noroviruses and developed reverse genetics, we now have the first opportunity to study human norovirus replication in a physiologically relevant system. We will focus on three areas: 1. C-type lectin receptors (CLRs): We have found that CLRs may work in concert with blood group antigens to allow norovirus infection. We will further dissect the role of CLRs in the norovirus life cycle. 2. Innate responses to infection: We have found that type I/III interferons restrict norovirus replication but that infection induces the COX-2/PGE pathway to promote replication. We will dissect the response to infection in the organoid system and characterise a novel virus-encoded regulator of the NF-kB system. 3. Trans-acting factors: We will examine their role of a number of host factors (VapA/B, Squle and PI4Kalpha) in norovirus replication and expand this study to an undertake an unbiased analysis of the human norovirus replication complex.