Our laboratory focuses on elucidating the fundamental molecular mechanisms underlying the replication of RNA viruses such as Influenza, Nipah, and SARS-CoV-2. Specifically, we aim to uncover the structural and functional properties of the RNA polymerase of these viruses, as well as the mechanisms of transcription, replication and trafficking of the viral RNA genome. Our objective is to obtain in-depth molecular insights into the replication mechanisms of these RNA viruses, ultimately paving the way to the development of novel antiviral approaches.
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Influenza virus replicase complex comprising a dimer of the viral RNA polymerase bridged by host ANP32A.
Influenza virus transcriptase bound to host RNA polymerase II performing cap-snatching.
Viruses with single-stranded RNA genomes represent a large group of viruses that includes numerous human, animal, and plant pathogens, such as influenza viruses, measles, rabies, Ebola, Nipah, Dengue, Zika, coronaviruses, and many others. A common feature of all these viruses is that they encode their RNA-dependent RNA polymerase, which is responsible for generating new copies of the viral genome through a complementary antigenome replicative intermediate. In the case of negative-sense RNA viruses, the RNA polymerase also transcribes the RNA genome into mRNA for the translation of viral proteins.
The primary focus of our laboratory is influenza viruses, which contain a segmented single-stranded negative-sense RNA genome. The RNA segments are assembled into viral ribonucleoprotein (vRNP) complexes, with the viral RNA polymerase bound to the partially complementary viral RNA termini, and the remaining part of the RNA bound to a scaffold of oligomeric viral nucleoprotein. It is in the context of these vRNPs that the RNA polymerase transcribes the RNA genome segments into mRNA and replicates them through a complementary RNA intermediate into new copies of the genome in the infected host cell nucleus.
We address questions ranging from how the influenza virus RNA polymerase switches between transcriptase and replicase functions in response to interactions with various host factors to how the RNA genome segments are exported from the nucleus and assembled into infectious progeny virus particles. We are also interested in uncovering the host range determinants of influenza viruses and understanding the effects of virus infection on the host cell, the molecular mechanisms of innate immune sensing, and host cell responses to viral infection.
We collaborate with structural biologists, physicists, chemists, and immunologists using an interdisciplinary approach that includes molecular and cell biology, structural biology (X-ray crystallography and cryo-electron microscopy), single-molecule and super-resolution microscopy, proteomics, and virology.
2023
A structural understanding of influenza virus genome replication.
Zhu, Z., Fodor, E. and Keown, J.R.
Trends in Microbiology – 31(3):308-319.
2022
Mapping inhibitory sites on the RNA polymerase of the 1918 pandemic influenza virus using nanobodies.
Keown, J.R., Zhu, Z., Carrique, L., Fan, H., Walker, A.P., Serna Martin, I., Pardon, E., Steyaert, J., Fodor, E. and Grimes, J.M.
Nature Communications – 13(1): 251.
2021
Structural insights into RNA polymerases of negative-sense RNA viruses.
te Velthuis, A.J.W., Grimes, J.M. and Fodor, E.
Nature Reviews Microbiology – 19(5):303-318.
2020
Host ANP32A mediates the assembly of the influenza virus replicase.
Carrique, L., Fan, H., Walker, A.P., Keown, J.R., Sharps, J., Staller, E., Barclay, W.S., Fodor, E. and Grimes, J.M.
Nature – 587(7835): 638-643.
2019
Structures of influenza A virus polymerase offer insight into viral genome replication.
Fan, H., Walker, A.P., Carrique, L., Keown, J.R., Serna Martin, I., Karia, D., Sharps, J., Hengrung, N., Pardon, E., Steyaert, J., Grimes, J.M. and Fodor, E.
Nature – 573(7773): 287-290.
2019
The structure of the influenza A virus genome.
Dadonaite, B., Gilbertson, B., Knight, M.L., Trifkovic, S., Rockman, S., Laederach, A., Brown, L.E., Fodor, E. and Bauer, D.L.V.
Nature Microbiology – 4(11): 1781-1789.
2018
Mini viral RNAs act as innate immune agonists during influenza virus infection.
te Velthuis, A.J.W., Long, J.C., Bauer, D.L.V., Fan, R.L.Y., Yen, H.L., Sharps, J., Siegers, J.Y., Killip, M.J., French, H., Oliva-Martín, M.J., Randall, R.E., de Wit, E., van Riel, D., Poon, L.L.M. and Fodor, E.
Nature Microbiology – 3:1234.
2015
Crystal structure of the RNA-dependent RNA polymerase from influenza C virus.
Hengrung, N., El Omari, K., Serna Martin, I., Vreede, F.T., Cusack, S., Rambo, R.P., Vonrhein, C., Bricogne, G., Stuart, D.I., Grimes, J.M. and Fodor, E.
Nature – 527(7576): 114-7.
Kuang-Yu Chen receives Wellcome Trust Early Career Award
September 2023
Contributions of Dr Kuang-Yu Chen to our understanding of host adaptation of SARS-CoV-2 earned her an esteemed Wellcome Trust grant.
Prof Ervin Fodor awarded an MRC programme award
December 2022
This prestigious 5 year award will support the group’s continued efforts to understand the molecular mechanisms underlying influenza virus transcription.