Project ID CM-HD2024_41


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Infectious DiseasesWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Infectious DiseasesWebsite

Additional Supervisor Dr. Daniel Bromage

Spatiotemporal decoding of cellular antiviral innate immune networks.

The outcome of virus infection is dictated by the balance between host-immune defence genes and host-dependency genes that suppress or promote virus replication, respectively. Cells naturally sense virus infection and rapidly induce expression of host-defence genes to prevent virus propagation. Amongst these genes are secreted second messenger molecules (e.g., interferon) that mobilise transcription of antiviral genes in neighbouring cells to establish an antiviral state. Unsurprisingly, viruses encode mechanisms to counteract and evade protective host-cell gene-expression changes. This project explores how host gene-expression differs in cells directly infected by a virus, versus in neighbouring bystander cells close to the infection focus.

Our data suggest that a tight race between a virus and the infected cell determines if neighbouring cells are protected. E.g., in influenza A virus (IAV) infected cells, expression of host-defence genes is suppressed, but likely activated in bystander cells, reflecting spatial gene-expression-waves around the point of initial infection. Working with IAV, HIV-1 or SARS-CoV-2, you will examine commonalities and variations in mechanisms of host-mediated antiviral control.

1) You will analyse gene-expression in different zones around an infection focus, using bulk and single-cell transcriptomics. This will identify genes whose transcription/ translation are induced in infected versus non-infected bystander cells. You will generate novel reporter cells allowing high-resolution microscopy to track infection-induced patterns of spatiotemporal gene-expression.
2) You will define how these expression waves are generated by disrupting viral mechanisms (e.g., using mutated viruses) that enable evasion from host-defence gene-expression and monitoring the consequences.
3) You will test if mutations in genes expressed in bystander cells associate with poor disease outcomes, as defined by published patient/ clinical databases.

In summary, through integrating molecular virology, time-resolved microscopy, biochemistry and transcriptomics (including network-analysis of sc- and bulk-transcriptomics), this project will challenge our thinking of cellular antiviral immunity, providing insight into novel therapeutic strategies.

Representative Publications

Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Goujon, C., Moncorgé, O., Bauby, H., Doyle, T., Ward, C.C., Schaller, T., Hué, S., Barclay, W.S., Schulz, R. and Malim, M.H. (2013). Nature 502, 559-562. DOI: 10.1038/nature12542 The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry. Doyle, T., Moncorgé, O., Bonaventure, B., Pollpeter, D., Lussignol, M., Tauziet, M., Apolonia, L., Catanese, M.-T. Goujon, C. and Malim, M.H. (2018). Nature Microbiology 3, 1369-1376. DOI: 10.1038/s41564-018-0273-9 HIV-1 Vpr induces widespread transcriptomic changes in CD4+ T-cells early post-infection. Bauby, H., Ward, C.C., Hugh-White, R., Swanson, C.M., Schulz, R., Goujon, C. and Malim, M.H. (2021). mBio 12, e01369-21. DOI: 10.1128/mBio.01369-21
Cell-Cycle Modulation of Transcription Termination Factor Sen1. Mischo HE, Chun Y, Harlen KM, Smalec BM, Dhir S, Churchman LS, Buratowski S. (2018) Mol Cell;70(2):312-326.e7. DOI: 10.1016/j.molcel.2018.03.010. Nuclear fate of yeast snoRNA is determined by co-transcriptional Rnt1 cleavage. Grzechnik P., Szczepaniak A.S., Dhir S., Pastucha A., Matuszek Z., Mischo H., Kufel J., Proudfoot N.J (2018) Nat. Commun.9(1):1783. DOI: 10.1038/s41467-018-04094-y. Homebrew: An economical and sensitive glassmilk-based nucleic-acid extraction method for SARS-CoV-2 diagnostics. Page R, Scourfield E, Ficarelli M, McKellar SW, Lee KL, Maguire TJA, Bouton C, Lista MJ, Neil SJD, Malim MH, Zuckerman M, Mischo HE, Martinez-Nunez RT. (2022) Cell Rep Methods;2(3):100186. DOI: 10.1016/j.crmeth.2022.100186.