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Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients

Devon J. Eddins, Junkai Yang, Astrid Kosters, Vincent D. Giacalone, Ximo Pechuan, Joshua D. Chandler, Benjamin R. Babcock, Jinyoung Eum, Mindy R. Hernández, Fathma Abdulkhader, Genoah L. Collins, Richard P. Ramonell, Christine Moussion, Darya Y. Orlova, Ignacio Sanz, F. Eun-Hyung Lee, Rabindra M. Tirouvanziam, View ORCID ProfileEliver E.B. Ghosn
doi: https://doi.org/10.1101/2021.06.02.446468
Devon J. Eddins
1Lowance Center for Human Immunology, Department of Medicine, Division of Immunology and Rheumatology, Emory University School of Medicine, Atlanta, GA 30322, USA
2Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
3Emory Vaccine Center, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA
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Junkai Yang
1Lowance Center for Human Immunology, Department of Medicine, Division of Immunology and Rheumatology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Astrid Kosters
1Lowance Center for Human Immunology, Department of Medicine, Division of Immunology and Rheumatology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Vincent D. Giacalone
2Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
4Center for CF & Airways Disease Research, Children’s Healthcare of Atlanta, Atlanta, 30322 GA, USA
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Ximo Pechuan
5Genentech, Inc., South San Francisco, California 94080, USA
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Joshua D. Chandler
2Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
4Center for CF & Airways Disease Research, Children’s Healthcare of Atlanta, Atlanta, 30322 GA, USA
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Benjamin R. Babcock
1Lowance Center for Human Immunology, Department of Medicine, Division of Immunology and Rheumatology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Jinyoung Eum
1Lowance Center for Human Immunology, Department of Medicine, Division of Immunology and Rheumatology, Emory University School of Medicine, Atlanta, GA 30322, USA
6Georgia Institute of Technology, Bioinformatics Graduate Program, Atlanta, GA 30332, USA
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Mindy R. Hernández
7Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
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Fathma Abdulkhader
1Lowance Center for Human Immunology, Department of Medicine, Division of Immunology and Rheumatology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Genoah L. Collins
2Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
4Center for CF & Airways Disease Research, Children’s Healthcare of Atlanta, Atlanta, 30322 GA, USA
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Richard P. Ramonell
7Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
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Christine Moussion
6Georgia Institute of Technology, Bioinformatics Graduate Program, Atlanta, GA 30332, USA
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Darya Y. Orlova
6Georgia Institute of Technology, Bioinformatics Graduate Program, Atlanta, GA 30332, USA
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Ignacio Sanz
1Lowance Center for Human Immunology, Department of Medicine, Division of Immunology and Rheumatology, Emory University School of Medicine, Atlanta, GA 30322, USA
3Emory Vaccine Center, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA
8Emory Autoimmunity Center of Excellence, Department of Medicine, Division of Rheumatology, Emory University School of Medicine, Atlanta, GA 30322, USA
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F. Eun-Hyung Lee
1Lowance Center for Human Immunology, Department of Medicine, Division of Immunology and Rheumatology, Emory University School of Medicine, Atlanta, GA 30322, USA
3Emory Vaccine Center, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA
7Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
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Rabindra M. Tirouvanziam
2Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
4Center for CF & Airways Disease Research, Children’s Healthcare of Atlanta, Atlanta, 30322 GA, USA
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Eliver E.B. Ghosn
1Lowance Center for Human Immunology, Department of Medicine, Division of Immunology and Rheumatology, Emory University School of Medicine, Atlanta, GA 30322, USA
2Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
3Emory Vaccine Center, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA
6Georgia Institute of Technology, Bioinformatics Graduate Program, Atlanta, GA 30332, USA
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  • ORCID record for Eliver E.B. Ghosn
  • For correspondence: eliver.ghosn@emory.edu
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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing COVID-19 pandemic have caused ~33 million cases and over 585,000 deaths in the United States alone. Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths being Black/African-American (AA) patients in some areas, yet targeted studies to delineate features of disease severity within this demographic are scant. Our multi-omics single-cell analyses of immune profiles from airways and matching blood samples of Black/AA patients revealed pronounced pulmonary neutrophilia and low viral burden as a hallmark of severe disease, where neutrophil phenotypes display advanced features of cytokine release syndrome and acute respiratory distress syndrome (ARDS). Cell-cell communication and trajectory analysis reveal a subset of circulating S100A12+/CXCR4+ mature neutrophils that infiltrate the lung via the IL-8/CXCR2 axis. Recruited neutrophils progress toward a transcriptionally active and pathogenic state characterized by exacerbated production of IL-8, IL-1β, IL-6, and CCL3/4 along with elevated levels of neutrophil elastase and myeloperoxidase. Inflammatory monocytes recruited via neutrophil-derived CCL3/4 also produce elevated neutrophil chemotactic factor IL-8, potentiating the sustained neutrophilia in the airways. The IL-8/CXCR2 axis emerges as a potential therapeutic target to reduce pathogenic neutrophilia and constrain ARDS in severe COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 03, 2021.
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Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients
Devon J. Eddins, Junkai Yang, Astrid Kosters, Vincent D. Giacalone, Ximo Pechuan, Joshua D. Chandler, Benjamin R. Babcock, Jinyoung Eum, Mindy R. Hernández, Fathma Abdulkhader, Genoah L. Collins, Richard P. Ramonell, Christine Moussion, Darya Y. Orlova, Ignacio Sanz, F. Eun-Hyung Lee, Rabindra M. Tirouvanziam, Eliver E.B. Ghosn
bioRxiv 2021.06.02.446468; doi: https://doi.org/10.1101/2021.06.02.446468
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Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients
Devon J. Eddins, Junkai Yang, Astrid Kosters, Vincent D. Giacalone, Ximo Pechuan, Joshua D. Chandler, Benjamin R. Babcock, Jinyoung Eum, Mindy R. Hernández, Fathma Abdulkhader, Genoah L. Collins, Richard P. Ramonell, Christine Moussion, Darya Y. Orlova, Ignacio Sanz, F. Eun-Hyung Lee, Rabindra M. Tirouvanziam, Eliver E.B. Ghosn
bioRxiv 2021.06.02.446468; doi: https://doi.org/10.1101/2021.06.02.446468

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