Journal Article

P selectin promotes SARS-CoV-2 interactions with platelets and the endothelium

Cohen, Scott B., Gamble, Jennifer R., Carr, Rebecca, Corcoran, Jennifer A., Dupuy, Alexander, Cole, Alexander J., Castanheira, Fernanda V.S., Aggarwal, Anupriya, Neely, G. Gregory, Loo, Lipin, Hesselson, Daniel, Passam, Freda H., Ison, Tim, Fenwick, Jemma, Chung, Felicity, Kong, Yvonne X., Kubes, Paul, Bui-Marinos, Maxwell P., Hagimola, Lejla, Turville, Stuart G., Du, Tian Y., Moreno, Cesar L., Ospina Stella, Alberto, Coleman, Paul R., Newton, Michelle

2025

Overview

The physiology of SARS-CoV-2 virus/host interactions is not well understood. To better understand host/virus interactions, we performed a CRISPR activation screen to identify host genes that confer resistance to authentic SARS-CoV-2. This highlighted 34 new candidate genes that may alter the course of infection. We validated that 7 of these genes can suppress authentic SARS-CoV-2 infection, including the innate immune receptor P selectin, which increases SARS-CoV-2 spike-dependent binding to cells, while protecting from infection. P selectin also promotes binding to SARS-CoV-2 variants, SARS-CoV-1, and Middle East respiratory syndrome spike proteins, suggesting a general role for P selectin in highly pathogenic coronavirus infections. Importantly, P selectin protein expression driven by synthetic mRNA can block SARS-CoV-2 infection. Naturally, P selectin is expressed on platelets, and we show that it promotes spike-mediated platelet aggregation. P selectin is also expressed on the endothelium, where SARS-CoV-2 spike interactions are also P selectin dependent. In vivo, SARS-CoV-2 uses P selectin to home to capillary beds where the virus interacts with platelets and endothelium, and blocking this interaction can clear vascular-associated pulmonary SARS-CoV-2.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Blood Platelets - metabolism / Blood Platelets - pathology / Blood Platelets - virology / Coronaviruses / COVID-19 - genetics / COVID-19 - immunology / COVID-19 - metabolism / COVID-19 - pathology / COVID-19 vaccines / CRISPR / Endothelium / Endothelium, Vascular - metabolism / Endothelium, Vascular - virology / Gene expression / Genes / Genomes / Health aspects / Humans / Immune response / Infections / Inflammation / Mice / Middle East respiratory syndrome / mRNA / P-Selectin - genetics / P-Selectin - immunology / P-Selectin - metabolism / Physiological aspects / Platelet aggregation / Proteins / Respiratory diseases / RNA / SARS-CoV-2 - metabolism / SARS-CoV-2 - physiology / Severe acute respiratory syndrome coronavirus 2 / Spike Glycoprotein, Coronavirus - genetics / Spike Glycoprotein, Coronavirus - metabolism