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, cytokines) 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. Influenza A virus (IAV), for example, interferes with host gene expression by inducing a transcript processing and termination defect. This mechanism is believed to deplete translatable mRNA from the cytoplasm and so prevent their translation into protein. Similarly, SARS-CoV-2, uses the non-structural protein 1 (NSP1) to inhibit translation of all cellular mRNA, but not of viral RNA. HIV-1, in contrast, does not profoundly disturb cellular gene expression programmes (although various host-encoded innate immune mechanisms are known to restrict HIV-1). This project explores how host gene-expression is affected during IAV, SARS CoV-2 or acute HIV-1 infection, and how these effects differ in cells directly infected by a virus, versus in neighbouring bystander cells close to the infection focus. Our data employing IAV infection suggest that a tight race between a virus and the infected cell determines if neighbouring cells are protected. E.g., in 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. By comparing three different viruses, this Thesis project will elaborate the various virus-specific mechanisms that hosts and viruses employ to counteract each other. Aim of the investigation (up to 150 words) State primary research question and where appropriate the primary hypotheses being tested. (145) Working with IAV, HIV-1 or SARS-CoV-2, this project examines commonalities and variations in mechanisms of host-mediated antiviral control. Analysis gene-expression in infected versus bystander cells to understand the differences between host-virus-sensing induced changes to gene expression of those changes affected by virus-host shut down mechanisms. Viral mechanisms to interfere with host-gene expression waves. Disruption of known virus-host-shut down mechanisms will allow to monitor the consequences of virus-host-shut down and potentially identifyadditional mechanisms. Contributions of host genes to restrict or promote viral propagation in infected cells. This aim 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.