Probing the molecular basis of translation-replication switching in pathogenic RNA viruses

Viruses that use a single strand of positive sense RNA (+ssRNA) as their genomes number a breadth of human pathogens including Zika virus (flavivirus), poliovirus (picornavirus), norovirus (calicivirus) and SARS-CoV2 (coronavirus). A number of key, fundamental questions regarding how these viruses regulate usage of their genomes remain. Answering these questions not only provides new biological insights into host-pathogen interactions but could prove critical in identifying new strategies for control. These viruses use the same molecule of RNA for protein expression and as a template for replication. However, these processes occur in opposing directions i.e. translation in a 5′-3′ direction and replication in a 3′-5′ direction. This therefore necessitates a "lifestyle switch" for any single RNA molecule in a cell, the details of which are unknown. We will use a multidisciplinary approach including in vitro reconstitution, cell biology and infection studies to determine how lifestyle switching of genome usage is regulated during infection by +ssRNA viruses. This work will lead to a new paradigm in our understanding of the evolution of genome organisation and function in an important class of pathogenic viruses.