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Nature medicine
01, 2022;28 (1): 201-211.

Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19.

Sarthak Sinha, Nicole L Rosin, Rohit Arora, Elodie Labit, Arzina Jaffer, Leslie Cao, Raquel Farias, Angela P Nguyen, Luiz G N de Almeida, Antoine Dufour, Amy Bromley, Braedon McDonald, Mark R Gillrie, Marvin J Fritzler, Bryan G Yipp, Jeff Biernaskie
Author Information
  1. Sarthak Sinha: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada. ORCID
  2. Nicole L Rosin: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada. nicole.rosin@ucalgary.ca. ORCID
  3. Rohit Arora: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
  4. Elodie Labit: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada. ORCID
  5. Arzina Jaffer: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada. ORCID
  6. Leslie Cao: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada. ORCID
  7. Raquel Farias: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  8. Angela P Nguyen: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. ORCID
  9. Luiz G N de Almeida: Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.
  10. Antoine Dufour: Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada. ORCID
  11. Amy Bromley: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
  12. Braedon McDonald: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  13. Mark R Gillrie: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. ORCID
  14. Marvin J Fritzler: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. ORCID
  15. Bryan G Yipp: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. bgyipp@ucalgary.ca. ORCID
  16. Jeff Biernaskie: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada. jeff.biernaskie@ucalgary.ca. ORCID
PMID: 34782790 DOI: 10.1038/s41591-021-01576-3

Abstract

Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin signaling. Dexamethasone during severe COVID-19 affected circulating neutrophils, altered IFN neutrophils, downregulated interferon-stimulated genes and activated IL-1R2 neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFN neutrophils and preferential steroid-induced immature neutrophil expansion, potentially affecting outcomes. Our single-cell atlas (see 'Data availability' section) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.

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MeSH Term

Adult
Aged
COVID-19
Cell Communication
Chromatography, Liquid
Cytokines
Dexamethasone
Down-Regulation
Female
Gene Regulatory Networks
Glucocorticoids
Humans
Immunity, Innate
Interferons
Male
Middle Aged
Neutrophils
Pneumonia, Bacterial
Prostaglandins
Proteomics
RNA-Seq
Respiratory Distress Syndrome
SARS-CoV-2
Severity of Illness Index
Sex Factors
Single-Cell Analysis
Tandem Mass Spectrometry
COVID-19 Drug Treatment

Chemicals

Cytokines
Glucocorticoids
Prostaglandins
Dexamethasone
Interferons
Journal Article Research Support, Non-U.S. Gov't

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