Insights into viral RNA synthesis by the influenza A virus and SARS-CoV-2 RNA polymerases

Influenza viruses cause substantial loss of life, and have been responsible for multiple pandemics in the past. Despite its prevalence, little is known about the molecular mechanisms of viral genome replication. Replication is carried out by viral RNA-dependent RNA polymerases (RdRPs) packaged in ribonucleoproteins. Multiple lines of evidence point towards oligomerisation of the RdRP being essential for replication, though how and why this occurs is currently unknown. This project will investigate RdRP oligomerisation further, using in vivo reconstitution techniques and in vitro trans-complementation assays to define the replicative complex of influenza virus. As the project develops, investigation into replication-associated host factors will likely become necessary to understand this highly host-dependent process. For example, ANP32A has been implicated in viral genome replication and host-adaption, though mechanisms for these roles are unknown. With resistance to antiviral drugs now widespread, better understanding of viral replication may help to define new targets in the future.

The ongoing COVID-19 pandemic is caused by the coronavirus SARS-CoV-2. This project will additionally investigate how the SARS-CoV-2 RdRP enzyme replicates the viral genome, by developing in vitro RNA synthesis assays using purified viral proteins. These studies will help to identify new drug targets which can be used to develop effective treatments for COVID-19.