Kavli Affiliate: Jean-Laurent Casanova, Charles M. Rice
| Authors: Jeremie Le Pen, Gabrielle Paniccia, Michael Bauer, H.-Heinrich Hoffmann, Volker Kinast, Marcela Moncada-Velez, Ana Pinharanda, Inna Ricardo-Lax, Ansgar F Stenzel, Edwin A Rosado-Olivieri, Alison W Ashbrook, Kenneth H Dinnon, William Doyle, Catherine Freije, Seon-Hui Hong, Danyel Lee, Tyler Lewy, Joseph M Luna, Avery Peace, Carltin Schmidt, Willia M Schneider, Roni Winkler, Chloe Larson, Timothy McGinn, Miriam-Rose Menezes, Lavoisier Ramos-Espiritu, Priyam Banerjee, John T Poirier, Francisco J Sanchez-Rivera, Qian Zhang, Jean-Laurent Casanova, Thomas S Carroll, J. Fraser Glickman, Eleftherios Michailidis, Brandon Razooky, Margaret R MacDonald and Charles M Rice
| Summary:
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 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 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 IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 over-expression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Our study contributes to understanding the association between PLSCR1 variants and severe COVID-19 cases reported in a recent GWAS.