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

Summary

A CRISPRa screen identified P-selectin as a host factor that increases spike-dependent binding yet protects against SARS-CoV-2 infection. P-selectin on platelets and endothelium mediates vascular interactions and homing of virus to capillary beds; synthetic mRNA–driven P-selectin expression blocks infection, and inhibiting P-selectin interactions clears pulmonary vascular virus in vivo.

Key Findings

• CRISPR activation screening identified 34 host genes modulating infection; seven, including P-selectin, suppressed authentic SARS-CoV-2 infection.
• P-selectin increased spike-dependent binding but conferred protection from infection; synthetic mRNA–driven P‑selectin expression blocked infection.
• P-selectin mediated spike interactions on platelets and endothelium, promoting platelet aggregation and vascular homing; blockade cleared pulmonary vascular virus in vivo.
• P-selectin facilitated binding across SARS-CoV-2 variants and other pathogenic coronaviruses (SARS-CoV-1, MERS), indicating broader relevance.

Clinical Implications

Targeting P-selectin–mediated interactions (e.g., with blockers or modulating expression) may reduce vascular sequestration and platelet aggregation in COVID‑19, opening avenues for adjunctive therapies alongside antivirals.

Limitations

• Preclinical models may not fully recapitulate human vascular physiology and safety of P-selectin modulation.
• Translation to clinical outcomes requires trials to assess efficacy and thrombotic/bleeding risk balance.

Future Directions

Evaluate pharmacologic P-selectin blockers or RNA-based modulation in relevant animal models and early-phase clinical studies to test reduction of vascular viral load, thrombosis, and hypoxemia.