Primary supervisor: Dr. M. Kikkert, LUMC, Leiden, the Netherlands
Title: To determine the role of picorna- and coronavirus proteases in manipulating cellular protein metabolism and innate immunity
Collaborators: Prof. A. Bowie, Trinity College Dublin, Ireland; Dr. R. Zahn, Janssen, Leiden, the Netherlands
Early Stage Researcher: Xavier Martinez Vendrells
Many positive strand RNA viruses encode one or more proteases that often have essential functions during viral replication. We hypothesize that many, if not all, of these viral proteases have accessory functions in suppressing innate immune signalling by cleaving essential cellular components in the cascade for example by exerting de-ubiquitinating activity. Additionally, our recent proteomics studies suggest that viral proteases can also influence the stability of many other cellular proteins, which have a function in diverse cellular processes. To understand how viral proteases influence cellular protein homeostasis, in collaboration with B7-UU, we will investigate activities of proteases encoded by picornaviruses (e.g.foot-and-mouth-disease virus (FMDV), mengovirus;), and coronaviruses (e.g. MERS-CoV, porcine epidemic diarrea virus (PEDV), feline infectious peritonitis virus (FIPV)). We aim to identify cellular substrates that are cleaved during infection and the mechanisms of immune suppression and manipulation of cellular protein metabolism exploited by these viruses. The ESR will use a combination of cleavage site predictions, proteomics screens, cell culture-based protein expression assays and viral mutagenesis studies (reverse genetics). The results will provide important new clues for exploration of novel antiviral strategies, for example innovations in vaccine design, in which immune evasive activities of viral proteases could be removed to increase efficacy. In this context, the ESR will, in collaboration with R. Zahn at Janssen in Leiden, investigate the immune evasive activities of adenovirus 26-encoded protease in order to explore possibilities for improvement of vaccine platforms developed at Janssen. In collaboration with Prof. Bowie in Dublin, the ESR will screen the influence of viral proteases (by over-expression or by using mutant viruses) on components of the innate immune- and inflammatory- response pathways using reporter assays developed and used by Trinity College Dublin.