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A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem inflammatory syndrome in children with severe myocarditis.
de Cevins, Camille; Luka, Marine; Smith, Nikaïa; Meynier, Sonia; Magérus, Aude; Carbone, Francesco; García-Paredes, Víctor; Barnabei, Laura; Batignes, Maxime; Boullé, Alexandre; Stolzenberg, Marie-Claude; Pérot, Brieuc P; Charbit, Bruno; Fali, Tinhinane; Pirabakaran, Vithura; Sorin, Boris; Riller, Quentin; Abdessalem, Ghaith; Beretta, Maxime; Grzelak, Ludivine; Goncalves, Pedro; Di Santo, James P; Mouquet, Hugo; Schwartz, Olivier; Zarhrate, Mohammed; Parisot, Mélanie; Bole-Feysot, Christine; Masson, Cécile; Cagnard, Nicolas; Corneau, Aurélien; Brunaud, Camille; Zhang, Shen-Ying; Casanova, Jean-Laurent; Bader-Meunier, Brigitte; Haroche, Julien; Melki, Isabelle; Lorrot, Mathie; Oualha, Mehdi; Moulin, Florence; Bonnet, Damien; Belhadjer, Zahra; Leruez, Marianne; Allali, Slimane; Gras-Leguen, Christèle; de Pontual, Loïc; Fischer, Alain; Duffy, Darragh; Rieux-Laucat, Fredéric; Toubiana, Julie; Ménager, Mickaël M.
  • de Cevins C; Université de Paris, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France.
  • Luka M; Molecular Biology and Genomics, Translational Sciences, Sanofi R&D, Chilly-Mazarin, France.
  • Smith N; Université de Paris, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France.
  • Meynier S; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, 75015 Paris, France.
  • Magérus A; Translational Immunology Lab, Department of Immunology, Institut Pasteur, 75015 Paris, France.
  • Carbone F; Université de Paris, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France.
  • García-Paredes V; Université de Paris, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France.
  • Barnabei L; Université de Paris, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France.
  • Batignes M; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, 75015 Paris, France.
  • Boullé A; Université de Paris, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France.
  • Stolzenberg MC; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, 75015 Paris, France.
  • Pérot BP; Université de Paris, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France.
  • Charbit B; Université de Paris, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France.
  • Fali T; Université de Paris, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France.
  • Pirabakaran V; Université de Paris, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France.
  • Sorin B; Université de Paris, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France.
  • Riller Q; Cytometry and Biomarkers UTechS, CRT, Institut Pasteur, 75015, Paris, France.
  • Abdessalem G; Université de Paris, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France.
  • Beretta M; Université de Paris, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France.
  • Grzelak L; Université de Paris, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France.
  • Goncalves P; Université de Paris, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France.
  • Di Santo JP; Université de Paris, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France.
  • Mouquet H; Humoral Immunology Laboratory, Department of Immunology, Institut Pasteur, 75015, Paris, France.
  • Schwartz O; INSERM U1222, Institut Pasteur, 75015, Paris, France.
  • Zarhrate M; Virus and Immunity Unit, Department of Virology, Institut Pasteur, 75015, Paris, France.
  • Parisot M; INSERM U1223, Institut Pasteur, 75015, Paris, France.
  • Bole-Feysot C; Innate Immunity Unit, Department of Immunology, Institut Pasteur, 75015, Paris, France.
  • Masson C; INSERM U1223, Institut Pasteur, 75015, Paris, France.
  • Cagnard N; Innate Immunity Unit, Department of Immunology, Institut Pasteur, 75015, Paris, France.
  • Corneau A; Humoral Immunology Laboratory, Department of Immunology, Institut Pasteur, 75015, Paris, France.
  • Brunaud C; INSERM U1222, Institut Pasteur, 75015, Paris, France.
  • Zhang SY; Virus and Immunity Unit, Department of Virology, Institut Pasteur, 75015, Paris, France.
  • Casanova JL; Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France.
  • Bader-Meunier B; Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France.
  • Haroche J; Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France.
  • Melki I; Bioinformatics Platform, Structure Fédérative de Recherche Necker, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.
  • Lorrot M; Bioinformatics Platform, Structure Fédérative de Recherche Necker, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.
  • Oualha M; Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, 75013 Paris, France.
  • Moulin F; Université de Paris, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France.
  • Bonnet D; Université de Paris, Imagine Institute, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, 75015 Paris, France.
  • Belhadjer Z; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
  • Leruez M; Université de Paris, Imagine Institute, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, 75015 Paris, France.
  • Allali S; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
  • Gras-Leguen C; Department of Paediatric Immuno-Haematology and Rheumatology, Reference Center for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (AP-HP), 75015 Paris, France.
  • de Pontual L; Department of Paediatric Immuno-Haematology and Rheumatology, Reference Center for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (AP-HP), 75015 Paris, France.
  • Fischer A; Department of Paediatric Immuno-Haematology and Rheumatology, Reference Center for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (AP-HP), 75015 Paris, France.
  • Duffy D; Department of Pediatrics, Robert-Debré University Hospital, AP-HP, Université de Paris, Paris, France.
  • Rieux-Laucat F; Department of Pediatrics, Armand-Trousseau University Hospital, AP-HP, 75012 Paris, France.
  • Toubiana J; Pediatric Intensive Care Unit, Necker-Enfants Malades University Hospital, AP-HP, Université de Paris, 75015 Paris, France.
  • Ménager MM; Pediatric Intensive Care Unit, Necker-Enfants Malades University Hospital, AP-HP, Université de Paris, 75015 Paris, France.
Med (N Y) ; 2(9): 1072-1092.e7, 2021 09 10.
Article in English | MEDLINE | ID: covidwho-1404796
ABSTRACT

BACKGROUND:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally milder than in adults, but a proportion of cases result in hyperinflammatory conditions often including myocarditis.

METHODS:

To better understand these cases, we applied a multiparametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. Plasma cytokine and chemokine levels and blood cellular composition were measured, alongside gene expression at the bulk and single-cell levels.

FINDINGS:

The most severe forms of multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 that resulted in myocarditis were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomics analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis characterized by sustained nuclear factor κB (NF-κB) activity and tumor necrosis factor alpha (TNF-α) signaling and associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type I and type II interferons, hyperinflammation, and response to oxidative stress related to increased HIF-1α and Vascular endothelial growth factor (VEGF) signaling.

CONCLUSIONS:

These results provide potential for a better understanding of disease pathophysiology.

FUNDING:

Agence National de la Recherche (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01; Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010; Laboratoire d'Excellence ''Milieu Intérieur," grant ANR-10-LABX-69-01; ANR-flash Covid19 "AIROCovid" and "CoVarImm"), Institut National de la Santé et de la Recherche Médicale (INSERM), and the "URGENCE COVID-19" fundraising campaign of Institut Pasteur.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 / Myocarditis Topics: Long Covid Limits: Adult / Child / Humans Language: English Journal: Med (N Y) Year: 2021 Document Type: Article Affiliation country: J.medj.2021.08.002

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 / Myocarditis Topics: Long Covid Limits: Adult / Child / Humans Language: English Journal: Med (N Y) Year: 2021 Document Type: Article Affiliation country: J.medj.2021.08.002