Reversible ADP-ribosylation signaling in the control of coronavirus infection

The interferon (IFN) immune response induces an antiviral state by triggering the expression of IFN-stimulated genes and is the primary line of defence against infection. The proteins encoded by these genes fulfil a variety of functions, including degradation of viral RNA and reduction in protein translation. Unsurprisingly, viruses have evolved compensatory mechanisms to suppress the IFN response. One such family of viruses is Coronaviridae, responsible for the current COVID-19 pandemic. Suppression of IFNs by Coronaviridae has been attributed to the macrodomain module present within the multidomain Nsp3 protein. The macrodomain functions as an ADP-ribosylhydrolase to neutralise the actions of the antiviral members of the poly(ADP-ribosyl)polymerase (PARP) family. However, the mechanisms through which antiviral PARPs and macrodomains impact the IFN response remain unclear. This proposal will provide a molecular understanding of how antiviral PARPs suppress coronavirus infection and how SARS-CoV-2 macrodomains oppose their activity to evade IFN signalling and promote viral replication. Furthermore, comparative analyses of the macrodomains from different coronaviruses and their impact on interferon response may explain the variations in their pathogenicity. Collectively, our studies will inform interferon-based disease management strategies to prevent spread within and between infected hosts and provide novel biomarkers of susceptibility and antiviral drug targets.