Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19

Aymeric Silvin; Nicolas Chapuis; Garett Dunsmore; Anne-Gaëlle Goubet; Agathe Dubuisson; Lisa Derosa; Carole Almire; Clémence Hénon; Olivier Kosmider; Nathalie Droin; Philippe Rameau; Cyril Catelain; Alexia Alfaro; Charles Dussiau; Chloé Friedrich; Elise Sourdeau; Nathalie Marin; Tali-Anne Szwebel; Delphine Cantin; Luc Mouthon; Didier Borderie; Marc Deloger; Delphine Bredel; Severine Mouraud; Damien Drubay; Muriel Andrieu; Anne-Sophie Lhonneur; Véronique Saada; Annabelle Stoclin; Christophe Willekens; Fanny Pommeret; Frank Griscelli; Lai Guan Ng; Zheng Zhang; Pierre Bost; Ido Amit; Fabrice Barlesi; Aurélien Marabelle; Frédéric Pène; Bertrand Gachot; Fabrice André; Laurence Zitvogel; Florent Ginhoux; Michaela Fontenay; Eric Solary

doi:10.1016/j.cell.2020.08.002

Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19

Cell. 2020 Sep 17;182(6):1401-1418.e18. doi: 10.1016/j.cell.2020.08.002. Epub 2020 Aug 5.

Authors

Aymeric Silvin¹, Nicolas Chapuis², Garett Dunsmore¹, Anne-Gaëlle Goubet¹, Agathe Dubuisson¹, Lisa Derosa³, Carole Almire⁴, Clémence Hénon⁵, Olivier Kosmider², Nathalie Droin⁶, Philippe Rameau⁷, Cyril Catelain⁷, Alexia Alfaro⁷, Charles Dussiau², Chloé Friedrich², Elise Sourdeau⁸, Nathalie Marin⁹, Tali-Anne Szwebel¹⁰, Delphine Cantin⁸, Luc Mouthon¹¹, Didier Borderie¹², Marc Deloger⁷, Delphine Bredel¹, Severine Mouraud¹, Damien Drubay¹³, Muriel Andrieu¹⁴, Anne-Sophie Lhonneur¹⁵, Véronique Saada¹⁶, Annabelle Stoclin¹⁷, Christophe Willekens¹⁸, Fanny Pommeret¹⁹, Frank Griscelli²⁰, Lai Guan Ng²¹, Zheng Zhang²², Pierre Bost²³, Ido Amit²⁴, Fabrice Barlesi¹⁹, Aurélien Marabelle²⁵, Frédéric Pène²⁶, Bertrand Gachot¹⁷, Fabrice André²⁷, Laurence Zitvogel²⁸, Florent Ginhoux²⁹, Michaela Fontenay³⁰, Eric Solary³¹

Affiliations

¹ INSERM U1015, Gustave Roussy Cancer Campus, Villejuif 94800, France.
² Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris 75006, France; Service d'Hématologie Biologique, AP-HP, Hôpital Cochin, Paris 75014, France.
³ INSERM U1015, Gustave Roussy Cancer Campus, Villejuif 94800, France; Département d'Oncologie Médicale, Gustave Roussy Cancer Campus, Villejuif 94800, France.
⁴ Service d'Hématologie Biologique, AP-HP, Hôpital Cochin, Paris 75014, France.
⁵ INSERM U981, Gustave Roussy Cancer Campus, Villejuif 94800, France.
⁶ INSERM U1287, Gustave Roussy Cancer Campus, Villejuif 94800, France; INSERM US23, CNRS UMS 3655, Gustave Roussy Cancer Campus, Villejuif 94800, France.
⁷ INSERM US23, CNRS UMS 3655, Gustave Roussy Cancer Campus, Villejuif 94800, France.
⁸ Service des Urgences, AP-HP, Hôpital Hôtel-Dieu, Paris 75014, France.
⁹ Service de Médecine Intensive et Réanimation, AP-HP, Hôpital Cochin, Paris 75014, France.
¹⁰ Service de Médecine Interne, AP-HP, Hôpital Cochin, Paris 75014, France.
¹¹ Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris 75006, France; Service de Médecine Interne, AP-HP, Hôpital Cochin, Paris 75014, France.
¹² Service de Diagnostic Biologique Automatisé, AP-HP, Hôpital Cochin, Paris 75014, France.
¹³ INSERM U1018, Gustave Roussy Cancer Campus, Villejuif 94800, France.
¹⁴ Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris 75006, France.
¹⁵ Laboratoire de Virologie, AP-HP, Hôpital Cochin, Paris 75014, France.
¹⁶ Département de Biologie et Pathologie, Gustave Roussy Cancer Campus, Villejuif 94800, France.
¹⁷ Service de Réanimation Médicale, Gustave Roussy Cancer Campus, Villejuif 94800, France.
¹⁸ INSERM U1287, Gustave Roussy Cancer Campus, Villejuif 94800, France; Département d'Hématologie, Gustave Roussy Cancer Campus, Villejuif 94800, France.
¹⁹ Département d'Oncologie Médicale, Gustave Roussy Cancer Campus, Villejuif 94800, France.
²⁰ Département d'Oncologie Médicale, Gustave Roussy Cancer Campus, Villejuif 94800, France; Département de Biologie et Pathologie, Gustave Roussy Cancer Campus, Villejuif 94800, France.
²¹ Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648, Singapore.
²² Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen 518112, Guangdong Province, China.
²³ Systems Biology Group, Department of Computational Biology and USR 3756, Institut Pasteur and CNRS, Paris 75015, France; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
²⁴ Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
²⁵ INSERM U1015, Gustave Roussy Cancer Campus, Villejuif 94800, France; Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy Cancer Campus, Villejuif 94800, France.
²⁶ Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris 75006, France; Service de Médecine Intensive et Réanimation, AP-HP, Hôpital Cochin, Paris 75014, France.
²⁷ Département d'Oncologie Médicale, Gustave Roussy Cancer Campus, Villejuif 94800, France; INSERM U981, Gustave Roussy Cancer Campus, Villejuif 94800, France; Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre 94270, France.
²⁸ INSERM U1015, Gustave Roussy Cancer Campus, Villejuif 94800, France; Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre 94270, France; Centre d'Investigation Clinique - Biothérapie, INSERM CICBT1428, Villejuif 94800, France.
²⁹ Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648, Singapore; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China; Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore 169856, Singapore. Electronic address: florent_ginhoux@immunol.a-star.edu.sg.
³⁰ Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris 75006, France; Service d'Hématologie Biologique, AP-HP, Hôpital Cochin, Paris 75014, France. Electronic address: michaela.fontenay@aphp.fr.
³¹ INSERM U1287, Gustave Roussy Cancer Campus, Villejuif 94800, France; Service de Réanimation Médicale, Gustave Roussy Cancer Campus, Villejuif 94800, France; Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre 94270, France. Electronic address: eric.solary@gustaveroussy.fr.

Abstract

Blood myeloid cells are known to be dysregulated in coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. It is unknown whether the innate myeloid response differs with disease severity and whether markers of innate immunity discriminate high-risk patients. Thus, we performed high-dimensional flow cytometry and single-cell RNA sequencing of COVID-19 patient peripheral blood cells and detected disappearance of non-classical CD14^LowCD16^High monocytes, accumulation of HLA-DR^Low classical monocytes (Human Leukocyte Antigen - DR isotype), and release of massive amounts of calprotectin (S100A8/S100A9) in severe cases. Immature CD10^LowCD101^-CXCR4^+/- neutrophils with an immunosuppressive profile accumulated in the blood and lungs, suggesting emergency myelopoiesis. Finally, we show that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe form of COVID-19, suggesting a predictive value that deserves prospective evaluation.

Keywords: COVID-19; S100A8; S100A9; SARS-CoV-2; calprotectin; emergency myelopoiesis; monocyte subsets; neutrophils; type I interferon.

MeSH terms

Betacoronavirus
COVID-19
Coronavirus Infections*
Coronavirus*
Flow Cytometry
Humans
Leukocyte L1 Antigen Complex
Monocytes
Myeloid Cells
Pandemics*
Pneumonia, Viral*
Prospective Studies
SARS-CoV-2

Substances

Leukocyte L1 Antigen Complex