Version 1: Meta-analysis of functional genomics studies reveals conserved cellular pathways required by viruses of pandemic concern

The COVID-19 pandemic illustrated the need to develop medical countermeasures against emerging infectious diseases. As viruses rely on cellular machinery for replication, host-directed antivirals (HDAs) may complement conventional antiviral strategies in a manner that offers broad-spectrum efficacy, including against novel viruses, and a potentially higher barrier to viral escape. Despite their potential, HDAs are under-represented as therapeutics, partly due to a lack of consensus on druggable host targets. To address this, we have performed a meta-analysis of 62 functional genomics studies involving viral families of pandemic concern, including Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, Phenuiviridae, Picronaviridae, Poxviridae and Togaviridae. Using a robust rank aggregation and protein-protein interaction network approach, host factors and cellular processes required by multiple virus families were identified, including the V-type ATPase complex, glycosaminoglycan synthesis, Golgi trafficking and endoplasmic reticulum membrane protein insertion. These pathways include those with known relevance to infection by some viruses while providing novel insights into the lifecycles of others. Therapeutic targeting of these top ranked host factors is also discussed, with several already possessing small molecule inhibitors, highlighting their therapeutic potential. Antivirals are an essential component of medical countermeasures against viral disease and fulfil a complementary role to vaccines. Importantly, they may provide the only therapeutic option for pathogens lacking effective vaccines or for individuals unable to be vaccinated. This analysis furthers our understanding of the virus-host interface and nominates cellular targets for the future development of HDAs as medical countermeasures for pandemic resilience.