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

Abstract

COVID-19 causes a clinical spectrum of acute and chronic illness and host / virus interactions are not completely understood. To identify host factors that can influence SARS-CoV-2 infection, we screened the human genome for genes that, when upregulated, alter the outcome of authentic SARS-CoV-2 infection. From this, we identify 34 new genes that can alter the course of infection, including the innate immune receptor P-selectin, which we show is a novel SARS-CoV-2 spike receptor. At the cellular level expression of P-selectin does not confer tropism for SARS-CoV-2, instead it acts to suppress infection. More broadly, P-selectin can also promote binding to SARS-CoV-2 variants, SARS-CoV-1 and MERS, acting as a general spike receptor for highly pathogenic coronaviruses. P-selectin is expressed on platelets and endothelium, and we confirm SARS-CoV-2 spike interactions with these cells are P-selectin-dependent and can occur under shear flow conditions. In vivo, authentic SARS-CoV-2 uses P-selectin to home to airway capillary beds where the virus interacts with the endothelium and platelets, and blocking this interaction can clear vascular-associated SARS-CoV-2 from the lung. Together we show for the first time that coronaviruses can use the leukocyte recruitment system to control tissue localization, and this fundamental insight may help us understand and control highly pathogenic coronavirus disease progression.

P-selectin Facilitates SARS-CoV-2 Spike 1 Subunit Attachment to Vesicular Endothelium and Platelets

“…Biolayer interference (BLI) revealed that the SARS-CoV-2 S1 bound to recombinant human SELP immobilized on streptavidin (SA) biosensors in the presence of 75 mM NaCl at an average affinity of 15.17 nM (Figure B). Although the SARS-CoV S1 protein has been reported to have the ability to interact with SELP, we did not detect the association signals under the same experimental conditions using BLI (data not shown). To explore the functional relevance of SELP to viral infection, we evaluated the adherence of S1 to HUVECs in the presence and absence of SELP.…”

“…Although the S1-mediated viral attachment is a crucial process for SARS-CoV-2 infection, by which many antiviral agents, such as neutralization antibodies, peptide antagonists, , and decoy nanoparticles, have been developed for COVID-19 treatment, however, neither the S1 adherence nor the spike pseudovirion infection can accurately reflect the authentic viral infection. Fortunately, this shortcoming was remedied by a study carried out by Moreno et al, in which they found live SARS-CoV-2 employed SELP to bind to airway capillary beds . Since the S1 protein induced endothelial inflammation (Figure ) and platelet aggregation in a dose-dependent manner, and because anti-SELP treatment significantly decreased the SARS-CoV-2 loads in vivo , the enhancement effect of SELP on S1 attachment may contribute to the pathogenesis of COVID-19.…”

“…Fortunately, this shortcoming was remedied by a study carried out by Moreno et al, in which they found live SARS-CoV-2 employed SELP to bind to airway capillary beds. 29 Since the S1 protein induced endothelial inflammation (Figure 4) and platelet aggregation in a dosedependent manner, 11 and because anti-SELP treatment significantly decreased the SARS-CoV-2 loads in vivo, 29 the enhancement effect of SELP on S1 attachment may contribute to the pathogenesis of COVID-19.…”