Identification of host dependency factors shared by multiple SARS-CoV-2 variants of concern

A key feature of RNA viruses, including SARS-CoV-2, is their high mutation rate, which allows them to develop resistance to vaccines and antiviral drugs targeting viral proteins. To overcome this downside, a strategy would be to target host factors, i.e. cell proteins required by the virus for its replication. However, it is still unclear whether cell responses induced by different SARS-CoV-2 variants are conserved and if the same core of host factors is exploited by different variants. We compared 3 variants of concern (VOC) that emerged during the first year of the pandemic and observed that the host transcriptional response was mostly conserved, differing only in the kinetics and magnitude. By CRISPR screening we identified the host genes required for infection by each VOC. These genes were associated with interferon and JAK/STAT pathway, autophagy, mTOR pathway, mitochondrial organisation and activity. Crucially, we failed to identify genes required by only one variant. We further validated our candidates with small molecules and repurposed FDA-approved drugs, which were effective against a novel variant emerged during the course of the study. We observed that SARS-CoV-2 infection induces a rapid spike in Reactive Oxygen Species (ROS) production, which can be targeted to block viral propagation. Our study identifies a core of host genes required for infection, and lays the foundation for general therapeutic strategies aimed at minimising emergence of novel resistant variants.