Severe COVID-19 Shares a Common Neutrophil Activation Signature with Other Acute Inflammatory States
Lena F. Schimke,
Alexandre H. C. Marques,
Gabriela Crispim Baiocchi,
Caroline Aliane de Souza Prado,
Dennyson Leandro M. Fonseca,
Paula Paccielli Freire,
Desirée Rodrigues Plaça,
Igor Salerno Filgueiras,
Ranieri Coelho Salgado,
Gabriel Jansen-Marques,
Antonio Edson Rocha Oliveira,
Jean Pierre Schatzmann Peron,
Gustavo Cabral-Miranda,
José Alexandre Marzagão Barbuto,
Niels Olsen Saraiva Camara,
Vera Lúcia Garcia Calich,
Hans D. Ochs,
Antonio Condino-Neto,
Katherine A. Overmyer,
Joshua J. Coon,
Joseph Balnis,
Ariel Jaitovich,
Jonas Schulte-Schrepping,
Thomas Ulas,
Joachim L. Schultze,
Helder I. Nakaya,
Igor Jurisica,
Otávio Cabral-Marques
Affiliations
Lena F. Schimke
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Alexandre H. C. Marques
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Gabriela Crispim Baiocchi
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Caroline Aliane de Souza Prado
Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Dennyson Leandro M. Fonseca
Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Paula Paccielli Freire
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Desirée Rodrigues Plaça
Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Igor Salerno Filgueiras
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Ranieri Coelho Salgado
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Gabriel Jansen-Marques
Information Systems, School of Arts, Sciences and Humanities, University of Sao Paulo, São Paulo 03828-000, Brazil
Antonio Edson Rocha Oliveira
Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Jean Pierre Schatzmann Peron
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Gustavo Cabral-Miranda
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
José Alexandre Marzagão Barbuto
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Niels Olsen Saraiva Camara
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Vera Lúcia Garcia Calich
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Hans D. Ochs
Department of Pediatrics, Seattle Children’s Research Institute, University of Washington School of Medicine, Seattle, WA 98101, USA
Antonio Condino-Neto
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Katherine A. Overmyer
National Center for Quantitative Biology of Complex Systems, Madison, WI 53562, USA
Joshua J. Coon
National Center for Quantitative Biology of Complex Systems, Madison, WI 53562, USA
Joseph Balnis
Division of Pulmonary and Critical Care Medicine, Albany Medical Center, Albany, NY 12208, USA
Ariel Jaitovich
Division of Pulmonary and Critical Care Medicine, Albany Medical Center, Albany, NY 12208, USA
Jonas Schulte-Schrepping
Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany
Thomas Ulas
Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Bonn, 53127 Bonn, Germany
Joachim L. Schultze
Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany
Helder I. Nakaya
Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Igor Jurisica
Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada
Otávio Cabral-Marques
Department of Imunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
Severe COVID-19 patients present a clinical and laboratory overlap with other hyperinflammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the underlying mechanisms of these conditions remain to be explored. Here, we investigated the transcriptome of 1596 individuals, including patients with COVID-19 in comparison to healthy controls, other acute inflammatory states (HLH, multisystem inflammatory syndrome in children [MIS-C], Kawasaki disease [KD]), and different respiratory infections (seasonal coronavirus, influenza, bacterial pneumonia). We observed that COVID-19 and HLH share immunological pathways (cytokine/chemokine signaling and neutrophil-mediated immune responses), including gene signatures that stratify COVID-19 patients admitted to the intensive care unit (ICU) and COVID-19_nonICU patients. Of note, among the common differentially expressed genes (DEG), there is a cluster of neutrophil-associated genes that reflects a generalized hyperinflammatory state since it is also dysregulated in patients with KD and bacterial pneumonia. These genes are dysregulated at the protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins that point to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.
