1. Infection of lung megakaryocytes and platelets by SARS-CoV-2 anticipate fatal COVID-19
- Author
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Aiwei Zhu, Fernando Real, Claude Capron, Arielle R. Rosenberg, Aymeric Silvin, Garett Dunsmore, Jaja Zhu, Andréa Cottoignies-Callamarte, Jean-Marc Massé, Pierre Moine, Simon Bessis, Mathieu Godement, Guillaume Geri, Jean-Daniel Chiche, Silvana Valdebenito, Sandrine Belouzard, Jean Dubuisson, Geoffroy Lorin de la Grandmaison, Sylvie Chevret, Florent Ginhoux, Eliseo A. Eugenin, Djillali Annane, Elisabeth Cramer Bordé, Morgane Bomsel, Institut Cochin [IC UM3 (UMR 8104 / U1016)], Université de Versailles Saint-Quentin-en-Yvelines [UVSQ], Hôpital Ambroise Paré [AP-HP], Hôpital Cochin [AP-HP], Immunologie anti-tumorale et immunothérapie des cancers [ITIC], Institut Gustave Roussy [IGR], Infection et inflammation [2I], The University of Texas Medical Branch [UTMB], Institut Pasteur de Lille, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL], Hôpital Raymond Poincaré [Garches], Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) [SBIM], Singapore Immunology Network [SIgN], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service d'Hématologie et d'Immunologie [AP-HP Hôpital Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de réanimation médicale polyvalente [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], The University of Texas Medical Branch (UTMB), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP), Université de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Agency for science, technology and research [Singapore] (A*STAR), ANR-20-COVI-0024,MUCOLUNG,Rôle des cellules pulmonaires infectées par le SRAS-CoV-2 et réponse humoral dans l' évolution du COVID-19: de la physiopathologie au test de médicaments candidats dans les modèles de cellules muqueuses(2020), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), School of Medicine [Shanghai Jiaotong University], Shanghai Jiaotong University, Accident Compensation Corporation, ACC, Fondation pour la Recherche Médicale, FRM, China Scholarship Council, CSC, 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., 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., and REAL, Fernando
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Blood Platelets ,Pharmacology ,Platelets ,SARS-CoV-2 ,Macrophages ,[SDV]Life Sciences [q-bio] ,Membrane Proteins ,RNA-Binding Proteins ,COVID-19 ,Thrombosis ,Cell Biology ,[SDV] Life Sciences [q-bio] ,Lung ,Megakaryocytes ,Cellular and Molecular Neuroscience ,Humans ,Molecular Medicine ,Molecular Biology - Abstract
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.
- Published
- 2022
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