Jérémie Le Pen, Gabrielle Paniccia, Volker Kinast, Marcela Moncada-Velez, Alison W Ashbrook, Michael Bauer, H-Heinrich Hoffmann, Ana Pinharanda, Inna Ricardo-Lax, Ansgar F Stenzel, Edwin A Rosado-Olivieri, 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-Espiritu, Priyam Banerjee, John T Poirier, Francisco J Sànchez-Rivera, Aurélie Cobat, Qian Zhang, Jean-Laurent Casanova, Thomas S Carroll, J Fraser Glickman, Eleftherios Michailidis, Brandon Razooky, Margaret R MacDonald, Charles M Rice
{"title":"一项全基因组阵列 CRISPR 筛选发现，PLSCR1 是 SARS-CoV-2 进入人体的内在屏障，而最近的病毒变种已经进化到可以抵御这一屏障。","authors":"Jérémie Le Pen, Gabrielle Paniccia, Volker Kinast, Marcela Moncada-Velez, Alison W Ashbrook, Michael Bauer, H-Heinrich Hoffmann, Ana Pinharanda, Inna Ricardo-Lax, Ansgar F Stenzel, Edwin A Rosado-Olivieri, 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-Espiritu, Priyam Banerjee, John T Poirier, Francisco J Sànchez-Rivera, Aurélie Cobat, Qian Zhang, Jean-Laurent Casanova, Thomas S Carroll, J Fraser Glickman, Eleftherios Michailidis, Brandon Razooky, Margaret R MacDonald, Charles M Rice","doi":"10.1371/journal.pbio.3002767","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8000,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11486371/pdf/","citationCount":"0","resultStr":"{\"title\":\"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.\",\"authors\":\"Jérémie Le Pen, Gabrielle Paniccia, Volker Kinast, Marcela Moncada-Velez, Alison W Ashbrook, Michael Bauer, H-Heinrich Hoffmann, Ana Pinharanda, Inna Ricardo-Lax, Ansgar F Stenzel, Edwin A Rosado-Olivieri, 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-Espiritu, Priyam Banerjee, John T Poirier, Francisco J Sànchez-Rivera, Aurélie Cobat, Qian Zhang, Jean-Laurent Casanova, Thomas S Carroll, J Fraser Glickman, Eleftherios Michailidis, Brandon Razooky, Margaret R MacDonald, Charles M Rice\",\"doi\":\"10.1371/journal.pbio.3002767\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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. 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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.
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.
期刊介绍：
PLOS Biology is the flagship journal of the Public Library of Science (PLOS) and focuses on publishing groundbreaking and relevant research in all areas of biological science. The journal features works at various scales, ranging from molecules to ecosystems, and also encourages interdisciplinary studies. PLOS Biology publishes articles that demonstrate exceptional significance, originality, and relevance, with a high standard of scientific rigor in methodology, reporting, and conclusions.
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