TY - JOUR
T1 - Infection of lung megakaryocytes and platelets by SARS-CoV-2 anticipate fatal COVID-19
AU - Zhu, Aiwei
AU - Real, Fernando
AU - Capron, Claude
AU - Rosenberg, Arielle R.
AU - Silvin, Aymeric
AU - Dunsmore, Garett
AU - Zhu, Jaja
AU - Cottoignies-Callamarte, Andréa
AU - Massé, Jean Marc
AU - Moine, Pierre
AU - Bessis, Simon
AU - Godement, Mathieu
AU - Geri, Guillaume
AU - Chiche, Jean Daniel
AU - Valdebenito, Silvana
AU - Belouzard, Sandrine
AU - Dubuisson, Jean
AU - Lorin de la Grandmaison, Geoffroy
AU - Chevret, Sylvie
AU - Ginhoux, Florent
AU - Eugenin, Eliseo A.
AU - Annane, Djillali
AU - Bordé, Elisabeth Cramer
AU - Bomsel, Morgane
N1 - Funding Information:
The authors thank Professor John F. Martin (University College of London, UK) for fruitful advice and discussion on the role of NRP1 receptor and VEGF in COVID19 and resultant therapeutical implications, and for English editing. The authors greatly acknowledge Karine Bailly and Muriel Andrieu of the Cochin Cytometry and Immunobiology Facility for cytokine analyses, as well as Thomas Guilbert from the Imag’IC facility for instruction on the IXplore Spin Confocal Imaging Microscope System (Olympus) and Livine Duban from Luminex corp for instruction on the Guava easyCyte 12HT base system (Millipore) during the COVID-19 confinement period. We also thank also Dr. Nicolas Chapuis (Hôpital Cochin, Paris, France) and Pr. Nicholas Heming (Hôpital Raymond Poincaré, Garches, France) for helpful discussion.
Funding Information:
Joint funding by the Agence Nationale de la Recherche (France) and Fondation pour la Recherche Médicale (France): Flash COVID ANR-FRM: ANR-20-COVI-0024. Funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. AZ was supported by the China Scholarship Council and ACC by the Fondation pour la Recherche Médicale.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/7
Y1 - 2022/7
N2 - SARS-CoV-2, although not being a circulatory virus, spread from the respiratory tract resulting in multiorgan failures and thrombotic complications, the hallmarks of fatal COVID-19. A convergent contributor could be platelets that beyond hemostatic functions can carry infectious viruses. Here, we profiled 52 patients with severe COVID-19 and demonstrated that circulating platelets of 19 out 20 non-survivor patients contain SARS-CoV-2 in robust correlation with fatal outcome. Platelets containing SARS-CoV-2 might originate from bone marrow and lung megakaryocytes (MKs), the platelet precursors, which were found infected by SARS-CoV-2 in COVID-19 autopsies. Accordingly, MKs undergoing shortened differentiation and expressing anti-viral IFITM1 and IFITM3 RNA as a sign of viral sensing were enriched in the circulation of deadly COVID-19. Infected MKs reach the lung concomitant with a specific MK-related cytokine storm rich in VEGF, PDGF and inflammatory molecules, anticipating fatal outcome. Lung macrophages capture SARS-CoV-2-containing platelets in vivo. The virus contained by platelets is infectious as capture of platelets carrying SARS-CoV-2 propagates infection to macrophages in vitro, in a process blocked by an anti-GPIIbIIIa drug. Altogether, platelets containing infectious SARS-CoV-2 alter COVID-19 pathogenesis and provide a powerful fatality marker. Clinical targeting of platelets might prevent viral spread, thrombus formation and exacerbated inflammation at once and increase survival in COVID-19.
AB - SARS-CoV-2, although not being a circulatory virus, spread from the respiratory tract resulting in multiorgan failures and thrombotic complications, the hallmarks of fatal COVID-19. A convergent contributor could be platelets that beyond hemostatic functions can carry infectious viruses. Here, we profiled 52 patients with severe COVID-19 and demonstrated that circulating platelets of 19 out 20 non-survivor patients contain SARS-CoV-2 in robust correlation with fatal outcome. Platelets containing SARS-CoV-2 might originate from bone marrow and lung megakaryocytes (MKs), the platelet precursors, which were found infected by SARS-CoV-2 in COVID-19 autopsies. Accordingly, MKs undergoing shortened differentiation and expressing anti-viral IFITM1 and IFITM3 RNA as a sign of viral sensing were enriched in the circulation of deadly COVID-19. Infected MKs reach the lung concomitant with a specific MK-related cytokine storm rich in VEGF, PDGF and inflammatory molecules, anticipating fatal outcome. Lung macrophages capture SARS-CoV-2-containing platelets in vivo. The virus contained by platelets is infectious as capture of platelets carrying SARS-CoV-2 propagates infection to macrophages in vitro, in a process blocked by an anti-GPIIbIIIa drug. Altogether, platelets containing infectious SARS-CoV-2 alter COVID-19 pathogenesis and provide a powerful fatality marker. Clinical targeting of platelets might prevent viral spread, thrombus formation and exacerbated inflammation at once and increase survival in COVID-19.
KW - COVID-19
KW - Lung
KW - Macrophages
KW - Megakaryocytes
KW - Platelets
KW - SARS-CoV-2
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UR - http://www.scopus.com/inward/citedby.url?scp=85132078452&partnerID=8YFLogxK
U2 - 10.1007/s00018-022-04318-x
DO - 10.1007/s00018-022-04318-x
M3 - Article
C2 - 35708858
AN - SCOPUS:85132078452
SN - 1420-682X
VL - 79
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 7
M1 - 365
ER -