From molecules to tissues: Host-cell responses to infection

Viruses are dependent on host resources to support their replication, from entry into cells to virus replication and assembly. Due to their limited coding capacity, viruses have evolved mechanisms to hijack, disarm and repurpose these host resources to promote their replication. These interactions span multiple levels, including different molecules (DNA, RNA and protein) and cellular pathways. The aim of this programme is to apply an unbiased evidence-based approach to identify common networks of host factors and host responses to infection that are conserved between divergent pathogens, unifying our understanding of how cells and tissues respond to virus infection. We will partner with the Rosalind Franklin Institute (RFI, Harwell Campus) and MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU, University of Dundee) to identify how these networks are formed, the repertoire of cellular and viral proteins involved, and their functional contribution to viral fitness in both cells and tissues that support infection and coinfection.
Knowledge gained from this programme will reveal the approaches employed by viruses to subvert host cells and whether these approaches are specific or broadly utilised across viruses. Discoveries from this programme will benefit the international virology community through the identification of new host-based therapeutic targets for intervention, reinforcing the reputation of the CVR as an international leading centre for virus research.

As obligate intracellular parasites, viruses are dependent on host resources to support their lifecycle, from entry into cells to gene expression, replication and virion assembly. Due to their limited coding capacity, viruses have evolved convergent mechanisms to hijack, disarm and repurpose host factors to promote their replication. These interactions span multiple levels, including different molecules (DNA, RNA and protein) and pathways. For example, multiple viruses hijack component proteins of the ubiquitin system to rapidly reshape the cellular proteome to create a favourable environment to support replication. As there are hundreds of viruses known to infect humans, these ‘master regulatory’ host factors (common to divergent pathogens) are also likely to control viral coinfections (either directly or indirectly), potentially influencing the outcome of virus transmission and disease severity.
While central to infection biology, the study of host–virus interactions has remained challenging due to: (i) the use of model systems that do not fully recapitulate the changes observed within infected cells or tissues; (ii) the use of protein and RNA levels as a measure or proxy for host change, without considering that these molecules exhibit activity changes and/or form distinct complexes with alternate functions in the same cell; (iii) the lack of suitable system-wide methods to map host interactions or responses to infection with high precision at molecular resolution; and (iv) the focus on single viruses, ignoring the interplay between viruses with shared cellular or tissue tropism. The goal of this integrated programme is to apply a system-wide evidence-based approach to identify convergent interaction networks between divergent viruses and their hosts, unifying our understanding of how cells respond to infection. In strategic partnership with the Rosalind Franklin Institute (RFI, Harwell Campus) and MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU, University of Dundee), we will: (i) identify the interfaces of interaction formed between viral nucleic acids and proteins within infected cells under alternate states of immune stimulation and elucidate their impact on viral replication; (ii) determine the repertoire of cellular and viral E3 ubiquitin ligases that actively reshape host responses to infection; (iii) develop 3D culture systems amenable to genetic manipulation to validate key host-virus interactions within human tissues that better recapitulate the microenvironment in which viruses have evolved to replicate; and (iv) investigate the impact of host-virus and virus-virus interactions on host responses to (co)infection and viral fitness within respiratory or skin epithelium. Knowledge gained from this programme will reveal the convergent mechanisms employed by different RNA and DNA viruses to subvert host cells that ultimately contribute to host susceptibility to infection and disease. Achieving the ambitious aims of this programme requires interdisciplinary expertise covering a wide range of viruses, model systems and technological platforms (proteomics, genomics, bioinformatics, chemical synthesis, biochemistry and advanced imaging). By bringing together specialist investigators (Chris Boutell, Adam Fletcher, Alfredo Castello, Pablo Murcia), we will apply new cutting-edge technologies to identify convergent interaction networks and host responses to infection between divergent viruses, unifying our understanding of how cells and tissues respond to infection. Discoveries from this programme will benefit the international virology community through the identification of new host-based therapeutic targets for intervention, reinforcing the reputation of the CVR as a leading international centre for infectious disease research.