biostudies-literatureLe Pen JSwiss National Science FoundationNCATS NIH HHSNIAID NIH HHSe3002767https://www.ebi.ac.uk/biostudies/studies/S-EPMC11486371biostudies-literatureUnknown22(9)Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of Coronavirus Disease 2019 (COVID-19) patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFPLoS biologyA genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist.PMC11486371R01 AI091707U19 AI111825R01 AI163029R01 AI161444UL1 TR001866203007MacDonald MRDinnon KHRicardo-Lax ISchmidt CPinharanda AMcGinn TPaniccia GLee DZhang QCarroll TSMoncada-Velez MYip EZBauer MFreije CASanchez-Rivera FJCobat ARazooky BLewy TDoyle WCAshbrook AWBanerjee PKinast VStenzel AFRosado-Olivieri EASchneider WMRamos-Espiritu LCasanova JLMenezes MRPoirier JTHoffmann HHMichailidis ELe Pen JLuna JMRice CMHong SHGlickman JFPeace AWinkler RLarson CfalseA genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist.Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of Coronavirus Disease 2019 (COVID-19) patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IF2024-01-01T00:00:00Z2024 Sep2026-07-15T09:36:31.074Z2025-04-06T09:33:54.991ZS-EPMC114863713931662310.1371/journal.pbio.3002767