A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist

• DOI: 10.1101/2024.02.16.580725
• Publication Date: 2024-02-20T02:30:11Z
• Authors: Jérémie Le Pen; Gabrielle Paniccia; Volker Kinast; Marcela Moncada-V...; Alison W. Ashbrook; Michael Bauer; H.-Heinrich Hoffmann; Ana Pinharanda; Inna Ricardo-Lax; Ansgar F. Stenzel; Edwin A. Rosado-O...; Kenneth H. Dinnon; William C. Doyle; Catherine A. Freije; Seon-Hui Hong; Danyel Lee; Tyler Lewy; Joseph M. Luna; Avery Peace; Carltin Schmidt; William M. Schneider; Roni Winkler; Elaine Z. Yip; Chloe Larson; Timothy McGinn; Miriam-Rose Menezes; Lavoisier Ramos-E...; Priyam Banerjee; John T. Poirier; Francisco J. Sànc...; Aurélie Cobat; Qian Zhang; Jean-Laurent Casa...; Thomas S. Carroll; J. Fraser Glickman; Eleftherios Micha...; Brandon Razooky; Margaret R. MacDo...; Charles M. Rice
• Keywords: HEK293 Cells; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Serine Endopeptidases; Humans; COVID-19; Clustered Regularly Interspaced Short Palindromic Repeats; Interferons; Virus Internalization; CRISPR-Cas Systems; Antigens, Differentiation; Research Article

Abstract Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted genome-wide arrayed CRISPR knockout screen presence absence IFN to identify human genes that influence SARS-CoV-2 infection. We then performed an integrated analysis interacting with SARS-CoV-2, drawing from selection 67 large-scale studies, including our own. identified 28 high relevance both genetic studies COVID-19 patients functional screens cell culture, many related pathway. Among these was IFN-stimulated gene PLSCR1 . did not require induction restrict contribute signaling. Instead, specifically restricted spike-mediated entry. The PLSCR1-mediated restriction alleviated by TMPRSS2 over-expression, suggesting primarily restricts endocytic entry route. In addition, recent variants have adapted circumvent barrier via currently undetermined mechanisms. Finally, investigate effects present humans discuss association between severe reported recently.