P selectin promotes SARS-CoV-2 interactions with platelets and the endothelium
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.
Authors
- Jemma Fenwick (ORCID: https://orcid.org/0009-0007-3753-8268)
- Alexander J. Cole (ORCID: https://orcid.org/0000-0001-9019-6884)
- Felicity Chung
- G. Gregory Neely (ORCID: https://orcid.org/0000-0002-1957-9732)
- Lipin Loo (ORCID: https://orcid.org/0000-0002-4112-1816)
- Cesar L. Moreno (ORCID: https://orcid.org/0000-0002-0876-0341)
- Alexander Dupuy (ORCID: https://orcid.org/0009-0009-8315-5641)
- Paul Coleman (ORCID: https://orcid.org/0000-0002-0976-0642)
- Rebecca Carr
- Fernanda V. S. Castanheira (ORCID: https://orcid.org/0000-0002-2024-7858)
- Jennifer A. Corcoran (ORCID: https://orcid.org/0000-0002-3764-0218)
- Maxwell P. Bui-Marinos (ORCID: https://orcid.org/0000-0001-9435-072X)
- Jennifer R. Gamble (ORCID: https://orcid.org/0000-0002-0179-9964)
- Lejla Hagimola (ORCID: https://orcid.org/0000-0001-6409-5131)
- Michelle Newton (ORCID: https://orcid.org/0000-0002-5522-0831)
- Stuart Turville (ORCID: https://orcid.org/0000-0003-1918-5343)
- Scott B. Cohen (ORCID: https://orcid.org/0000-0003-3741-1965)
- Yvonne Kong (ORCID: https://orcid.org/0000-0002-1972-0441)
- Freda Passam (ORCID: https://orcid.org/0000-0003-4584-2044)
- Anupriya Aggarwal (ORCID: https://orcid.org/0000-0001-8678-0519)
- Daniel Hesselson (ORCID: https://orcid.org/0000-0002-8675-9426)
- Paul Kubes (ORCID: https://orcid.org/0000-0002-2835-4244)
- Tian Y. Du (ORCID: https://orcid.org/0000-0002-0674-361X)
- Alberto Ospina Stella (ORCID: https://orcid.org/0000-0002-0972-8693)
- Tim Ison
Institutions
- The University of Sydney (AU)
- Children's Medical Research Institute (AU)
- University of Calgary (CA)
- Centenary Institute (AU)
- The Heart Research Institute (AU)
- UNSW Sydney (AU)
- Centenary College of Louisiana (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-11-16
- DOI
- https://doi.org/10.1172/jci184514
- Primary Topic
- COVID-19 Clinical Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Canadian Institutes of Health Research
- Medical Research Council
- National Health and Medical Research Council