tetano
Editor, Senior Moderator
PLoS Biol
. 2024 Sep 24;22(9):e3002767.
doi: 10.1371/journal.pbio.3002767. Online ahead of print. 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
Jérémie Le Pen[SUP] 1 [/SUP], Gabrielle Paniccia[SUP] 1 [/SUP], Volker Kinast[SUP] 2 3 [/SUP], Marcela Moncada-Velez[SUP] 4 [/SUP], Alison W Ashbrook[SUP] 1 [/SUP], Michael Bauer[SUP] 1 [/SUP], H-Heinrich Hoffmann[SUP] 1 [/SUP], Ana Pinharanda[SUP] 5 [/SUP], Inna Ricardo-Lax[SUP] 1 [/SUP], Ansgar F Stenzel[SUP] 1 [/SUP], Edwin A Rosado-Olivieri[SUP] 6 [/SUP], Kenneth H Dinnon 3rd[SUP] 1 [/SUP], William C Doyle[SUP] 1 [/SUP], Catherine A Freije[SUP] 1 [/SUP], Seon-Hui Hong[SUP] 1 [/SUP], Danyel Lee[SUP] 4 7 8 [/SUP], Tyler Lewy[SUP] 1 [/SUP], Joseph M Luna[SUP] 1 [/SUP], Avery Peace[SUP] 1 [/SUP], Carltin Schmidt[SUP] 4 [/SUP], William M Schneider[SUP] 1 [/SUP], Roni Winkler[SUP] 1 [/SUP], Elaine Z Yip[SUP] 1 [/SUP], Chloe Larson[SUP] 9 [/SUP], Timothy McGinn[SUP] 9 [/SUP], Miriam-Rose Menezes[SUP] 9 [/SUP], Lavoisier Ramos-Espiritu[SUP] 9 [/SUP], Priyam Banerjee[SUP] 10 [/SUP], John T Poirier[SUP] 11 [/SUP], Francisco J Sànchez-Rivera[SUP] 12 13 [/SUP], Aurélie Cobat[SUP] 4 7 8 [/SUP], Qian Zhang[SUP] 4 7 8 [/SUP], Jean-Laurent Casanova[SUP] 4 7 8 14 15 [/SUP], Thomas S Carroll[SUP] 16 [/SUP], J Fraser Glickman[SUP] 9 [/SUP], Eleftherios Michailidis[SUP] 1 [/SUP], Brandon Razooky[SUP] 1 [/SUP], Margaret R MacDonald[SUP] 1 [/SUP], Charles M Rice[SUP] 1 [/SUP]
Affiliations
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 IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 overexpression, 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. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently.
. 2024 Sep 24;22(9):e3002767.
doi: 10.1371/journal.pbio.3002767. Online ahead of print. 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
Jérémie Le Pen[SUP] 1 [/SUP], Gabrielle Paniccia[SUP] 1 [/SUP], Volker Kinast[SUP] 2 3 [/SUP], Marcela Moncada-Velez[SUP] 4 [/SUP], Alison W Ashbrook[SUP] 1 [/SUP], Michael Bauer[SUP] 1 [/SUP], H-Heinrich Hoffmann[SUP] 1 [/SUP], Ana Pinharanda[SUP] 5 [/SUP], Inna Ricardo-Lax[SUP] 1 [/SUP], Ansgar F Stenzel[SUP] 1 [/SUP], Edwin A Rosado-Olivieri[SUP] 6 [/SUP], Kenneth H Dinnon 3rd[SUP] 1 [/SUP], William C Doyle[SUP] 1 [/SUP], Catherine A Freije[SUP] 1 [/SUP], Seon-Hui Hong[SUP] 1 [/SUP], Danyel Lee[SUP] 4 7 8 [/SUP], Tyler Lewy[SUP] 1 [/SUP], Joseph M Luna[SUP] 1 [/SUP], Avery Peace[SUP] 1 [/SUP], Carltin Schmidt[SUP] 4 [/SUP], William M Schneider[SUP] 1 [/SUP], Roni Winkler[SUP] 1 [/SUP], Elaine Z Yip[SUP] 1 [/SUP], Chloe Larson[SUP] 9 [/SUP], Timothy McGinn[SUP] 9 [/SUP], Miriam-Rose Menezes[SUP] 9 [/SUP], Lavoisier Ramos-Espiritu[SUP] 9 [/SUP], Priyam Banerjee[SUP] 10 [/SUP], John T Poirier[SUP] 11 [/SUP], Francisco J Sànchez-Rivera[SUP] 12 13 [/SUP], Aurélie Cobat[SUP] 4 7 8 [/SUP], Qian Zhang[SUP] 4 7 8 [/SUP], Jean-Laurent Casanova[SUP] 4 7 8 14 15 [/SUP], Thomas S Carroll[SUP] 16 [/SUP], J Fraser Glickman[SUP] 9 [/SUP], Eleftherios Michailidis[SUP] 1 [/SUP], Brandon Razooky[SUP] 1 [/SUP], Margaret R MacDonald[SUP] 1 [/SUP], Charles M Rice[SUP] 1 [/SUP]
Affiliations
- PMID: 39316623
- DOI: 10.1371/journal.pbio.3002767
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 IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 overexpression, 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. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently.