Understanding the role of the viral polymerase in influenza virus virulence (360G-Wellcome-206579_Z_17_Z)

The development of novel strategies against influenza viruses depends on our understanding of influenza virus replication and pathogenicity. The former largely depends on the activity of the viral RNA polymerase, which copies and transcribes the viral genome, while the latter is multifaceted and influenced by both viral and host factors. Interestingly, recent findings show that the RNA polymerases of highly pathogenic influenza A viruses produce short RNAs, or mini viral RNAs (mvRNAs), which are non-contiguous in the viral genome and strong inducers of the interferon response. Because they are not made by RNA polymerases of seasonal influenza strains, mvRNA synthesis may be a transformational advance in our understanding of the ‘cytokine storm’ that underlies the pathogenicity of virulent influenza viruses. Unfortunately, our basic understanding of the influenza RNA polymerase is limited and it is unclear how the mvRNAs are made. I here plan to use single-molecule FRET, deep-sequencing and structure-guided mutagenesis to advance our basic understanding of influenza virus RNA synthesis, focussing on the molecular mechanics behind i) influenza transcription initiation, ii) the differences between the RNA polymerases of highly pathogenic and seasonal influenza strains, and iii) the action of influenza inhibitors that target the RNA polymerase.