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Author Notes:

Eliver E. B. Ghosn, Lowance Center for Human Immunology, Health Sciences Research Building, 1760 Haygood Dr NE, E240, Atlanta, GA 30322; eliver.ghosn@emory.edu

J.Y. and A.K. contributed equally to this study.

Contribution: D.J.E. contributed to conceptualization, methodology, investigation, formal analysis, data curation, visualization, and wrote the original draft and reviewed and edited the manuscript; J.Y. contributed to methodology, formal analysis, data curation, visualization, and reviewed and edited the manuscript; A.K. contributed to methodology, investigation, data curation, and reviewed and edited the manuscript; V.D.G. contributed to methodology, formal analysis, investigation, data curation, and reviewed and edited the manuscript; X.P-G. contributed to methodology, formal analysis, data curation, visualization, and reviewed and edited the manuscript; J.D.C. contributed to methodology, formal analysis, investigation, data curation, and reviewed and edited the manuscript; J.E. contributed to formal analysis and visualization; B.R.B. contributed to investigation and data curation; B.S.D. contributed to investigation, data curation, and formal analysis; M.R.H. contributed to resources; F.A. and G.L.C. contributed to investigation; R.P.R. contributed to resources, data curation, and reviewed and edited the manuscript; D.Y.O. contributed to methodology and data curation; I.S. contributed to resources; C.M. contributed to methodology, and formal analysis; F.E.H.L. contributed to methodology, data curation, resources, and reviewed and edited the manuscript; R.M.T. contributed to methodology, formal analysis, data curation, resources, and reviewed and edited the manuscript; E.E.B.G. contributed to conceptualization, methodology, formal analysis, resources, data curation, wrote the original draft, and contributed to visualization, supervision, project administration, and funding acquisition; and all authors discussed the results and read and approved the final manuscript.

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Research Funding:

This study was supported by the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases R01AI123126 and R01AI123126-05S1 (E.E.B.G.), NIH National Heart, Lung, and Blood Institute T32-HL116271 to 07 (R.P.R.), the Program for Breakthrough Biomedical Research (E.E.B.G.), and the Lowance Center for Human Immunology (E.E.B.G.). D.J.E. was partially supported by Emory's Laney Graduate School Fellowship, and J.D.C. was supported in part by CF@LANTA, a component of Emory University and Children's Healthcare of Atlanta. The graphical abstract and supplemental Figure 6A were generated, in part, using BioRender. The authors thank Keivan Zandi, Ann Chahroudi, Nils Schoof, Kira Moresco, and Stacy Heilman of the Department of Pediatrics (Emory University), along with the Emory Biosafety Officers Kalpana Rengarajan and Esmeralda Meyer for their assistance in setting up the BSL3 facility and kindly providing SARS-CoV-2 viral stocks. The authors also thank Nadia Roan (Gladstone Institutes/University of California, San Francisco) and Sulggi Lee (University of California, San Francisco) for their helpful discussions. Flow cytometry data were collected at Emory's Pediatrics/Winship Flow Cytometry Core (access supported in part by Children's Healthcare of Atlanta). The authors acknowledge the Genomic Cores at the Yerkes Non-Human Primate Research Center at Emory University (NIH Office of The Director, NIH P51 OD011132 and S10 OD026799), Baylor College of Medicine, and Parker H. Petit Institute for Bioengineering and Bioscience at the Georgia Institute of Technology for single-cell library sequencing. The authors are grateful for the efforts of Sang N. Le, John Varghese, Anum Jalal, Saeyun Lee, and Rahul Patel, who also contributed to the patient recruitment. The authors also thank the nurses, staff, and providers in the 71 ICU at Emory University Hospital Midtown, the medical ICU in Emory Decatur Hospital, the 5G/6G ICU in Emory University Hospital, and the ICU in Emory Saint Joseph's Hospital for their dedication and commitment during the COVID-19 pandemic. The authors thank all the healthy individuals, patients, and their families for their participation in this study, without whom the work would not have been possible.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Hematology
  • DISCRIMINATE SEVERE
  • ETHNIC DISPARITIES
  • ACTIVATION
  • SENSITIVITY
  • BINDING
  • PROTEIN
  • TARGET
  • MD-2

Transcriptional reprogramming of infiltrating neutrophils drives lung pathology in severe COVID-19 despite low viral load

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Journal Title:

BLOOD ADVANCES

Volume:

Volume 7, Number 5

Publisher:

, Pages 778-799

Type of Work:

Article | Final Publisher PDF

Abstract:

Troubling disparities in COVID-19–associated mortality emerged early, with nearly 70% of deaths confined to Black/African American (AA) patients in some areas. However, targeted studies on this vulnerable population are scarce. Here, we applied multiomics single-cell analyses of immune profiles from matching airways and blood samples of Black/AA patients during acute SARS-CoV-2 infection. Transcriptional reprogramming of infiltrating IFITM2+/S100A12+ mature neutrophils, likely recruited via the IL-8/CXCR2 axis, leads to persistent and self-sustaining pulmonary neutrophilia with advanced features of acute respiratory distress syndrome (ARDS) despite low viral load in the airways. In addition, exacerbated neutrophil production of IL-8, IL-1β, IL-6, and CCL3/4, along with elevated levels of neutrophil elastase and myeloperoxidase, were the hallmarks of transcriptionally active and pathogenic airway neutrophilia. Although our analysis was limited to Black/AA patients and was not designed as a comparative study across different ethnicities, we present an unprecedented in-depth analysis of the immunopathology that leads to acute respiratory distress syndrome in a well-defined patient population disproportionally affected by severe COVID-19.

Copyright information:

© 2023 by The American Society of Hematology

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/rdf).
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