A structural and functional understanding Influenza virus mRNA production in the context of the transcriptionally functional ribonucleoprotein (RNP) particle.

Influenza is a major public health burden, with seasonal outbreaks contributing significantly to mortality worldwide, and the emergence of pandemic strains remaining an ever-present threat.

Influenza drug and vaccine conception efforts are aided by a thorough understanding of its molecular biology.A key aspect of the influenza lifecycle is the production of capped and poly-adenylated messenger RNA by the heterotrimeric influenza polymerase (FluPol).

Ground-breaking work performed by the Cusack lab, has described with residue-resolution detail, the FluPol structures that form during transcription of short, non-nucleoprotein (NP) bound viral RNAs (vRNAs).

However, influenza transcription in vivo occurs within the ribonucleoprotein (RNP) particle and does not utilise naked genome segments.

The viral RNP (vRNP) is a super-helical complex composed FluPol bound at the conserved 3′ and 5′ ends of a vRNA, which is coated with NP.

The current low-resolution structures provide little information about the molecular details of vRNP function, particularly, how NPs interact with FluPol and the vRNA template.Via an inter-disciplinary approach, I will utilise cryo-electron microscopy methods, transcription assays and single-molecule fluorescence, to obtain the first high resolution structure of a dynamic influenza vRNP, with a particular focus on the spatial organisation of NPs relative to FluPol.

In addition to this work facilitating future influenza drug research, it will provide a basis to investigate the vRNP during other lifecycle stages and act as proof-of-principle for study of other viral protein-RNA complexes, such as those from corona-, arena- and bunyaviruses.Work will be performed in the groups of Stephen Cusack and Olivier Duss based at EMBL Grenoble and Heidelberg, respectively.

Here, I will have access to world-leading facilities and training opportunities, supporting my growth as an independent researcher and an expert in RNA virus structural biology.