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Molecular mechanisms of influenza virus replication


   Sir William Dunn School of Pathology

  Prof E Fodor  Friday, December 09, 2022  Competition Funded PhD Project (Students Worldwide)

About the Project

Influenza viruses are important human and animal pathogens; they cause widespread clinical and veterinary disease and have a considerable economic impact. Our laboratory focuses on the fundamental molecular mechanisms of influenza virus replication, aiming to understand the molecular determinants of host range and virulence of influenza viruses.

Specifically, we address questions ranging from how the influenza virus RNA polymerase transcribes and replicates the segmented negative-sense viral RNA genome in the nucleus of the infected cell to how the RNA genome is exported from the nucleus and assembled into infectious progeny virus particles. We are also interested in the role of host factors in viral replication as well as in understanding the effects of virus infection on the host cell, the molecular mechanisms of innate immune sensing and host cell responses to viral infection. Our group collaborates with structural biologists, physicists, chemists and immunologists using an interdisciplinary approach including molecular and cell biology, proteomics, single molecule and super-resolution microscopy, structural biology (x-ray crystallography and cryo-electron microscopy), and virology (reverse genetics).

This project builds on our recent success in the structural and functional characterization of the influenza virus RNA polymerase and its role in the replication of the viral RNA genome and transcription of viral genes. To replicate the viral RNA genome the RNA polymerase forms a complex with a host ANP32 protein (Carrique et al Nature 2020), while to transcribe viral genes it associates with host RNA polymerase II (Serna Martin et al Mol Cell 2018). The project aims at defining the wider context of these complexes in the nucleus of infected cells using a combination of cross-linking and proximity labelling approaches followed by mass spectrometry to identify the macromolecular complexes involved. The role of identified factors will be evaluated using gene-silencing or CRISPR-Cas9 gene knock-outs and viral infections and explored further by using recombinant proteins, pull-down assays, and structural biology. We will offer training in all the techniques required to carry out the project.  


Funding Notes

4 Year DPhil Prize Studentships cover full University fees, a tax free enhanced stipend of ~£20,168 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

Keown JR, Zhu Z, Carrique L, Fan H, Walker AP, Serna Martin I, Pardon E, Steyaert J, Fodor E, Grimes JM (2022) Mapping inhibitory sites on the RNA polymerase of the 1918 pandemic influenza virus using nanobodies. Nat Commun 13(1):251.
te Velthuis AJW, Grimes MJ, Fodor E (2021) Structural insights into RNA polymerases of negative-sense RNA viruses. Nat Rev Microbiol 19(5):303-318.
Carrique L, Fan H, Walker AP, Keown JR, Sharps J, Staller E, Barclay WS, Fodor E, Grimes JM (2020) Host ANP32A mediates the assembly of the influenza virus replicase. Nature 587(7835):638-643.
Fan H, Walker AP, Carrique L, Keown JR, Serna Martin I, Karia D, Sharps J, Hengrung N, Pardon E, Steyaert J, Grimes JM and Fodor E (2019) Structures of influenza A virus RNA polymerase offer insight into viral genome replication. Nature 573(7773):287-290.
Serna Martin I, Hengrung N, Renner M, Sharps J, Martínez-Alonso M, Masiulis S, Grimes JM, Fodor E (2018) A Mechanism for the Activation of the Influenza Virus Transcriptase. Mol Cell 70:1101-1110.

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