Supervisors: Ervin Fodor and Dr Kuang-Yu Chen

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 their RNA polymerases, as well as the mechanisms of viral gene transcription and the replication and trafficking of viral RNA genomes. Our objective is to gain molecular insights into RNA virus replication, ultimately paving the way for the development of novel antivirals.

This project focuses primarily on influenza A virus, while selected studies may extend to SARS-CoV-2 to identify conserved mechanisms of replication among medically important RNA viruses. Despite their distinct replication strategies, influenza virus and SARS-CoV-2 both rely on a virally encoded RNA-dependent RNA polymerase to transcribe and replicate their RNA genomes through coordinated interactions with viral and host factors. While considerable progress has been made in characterising the structures and functions of these viral replication machineries, important questions remain regarding how replication complexes are assembled, how viral RNAs and proteins are trafficked within infected cells, and how host pathways regulate these processes.

Building on recent advances from the Fodor and Grimes laboratories, this graduate project will investigate: (1) how viral replication complexes are assembled and organised within infected cells; (2) how viral RNAs are synthesised, processed and associated with viral proteins to generate replication and assembly intermediates; (3) how viral genomes and replication components are trafficked to and from sites of RNA synthesis and virion assembly; and (4) how host factors regulate these processes and influence viral replication, host adaptation and pathogenicity.

The project will adopt a multidisciplinary approach combining biochemical reconstitution, cell-based assays, proteomics, viral reverse genetics and advanced imaging. Cross-linking and proximity labelling coupled with mass spectrometry will be used to identify viral and host components involved in RNA synthesis and trafficking, whose functions will be investigated using gene silencing or CRISPR-Cas9-mediated gene editing in the context of infection. Further studies will involve recombinant protein expression, interaction assays and structural analyses in collaboration with the Grimes laboratory. Comprehensive training in the techniques required for the project will be provided.

Relevant publications

Rep A, Wang F, Chen KY, Carrique L, Sharps J, Grimes JM, Fodor E (2026) Regulatory hotspot on the influenza A virus polymerase revealed through the structure of the NEP-polymerase complex.  Sci Adv 12(4):eaeb4073.

Staller E, Carrique L, Swann OC, Fan H, Keown JR, Sheppard CM, Barclay WS, Grimes JM, Fodor E (2024) Structures of H5N1 influenza polymerase with ANP32B reveal mechanisms of genome replication and host adaptation. Nat Commun 15(1):4123.

Zhu Z, Fan H, Fodor E (2023) Defining the minimal components of the influenza A virus replication machinery via an in vitro reconstitution system. PLoS Biol 21(11):e3002370.

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.