Journal
NATURE MEDICINE
Volume 28, Issue 1, Pages 201-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-021-01576-3
Keywords
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Funding
- Thistledown Foundation
- Calgary Firefighters Burn Treatment Society
- CIHR Vanier doctoral scholarship
- Alberta Innovates doctoral scholarship
- Killam doctoral scholarship
- Alberta Children's Hospital Research Institute postdoctoral fellowship
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New findings illuminate the molecular mechanisms of dexamethasone action in severe COVID-19 patients, highlighting the expansion of distinct neutrophil states and altered immune dynamics. These results pave the way for the development of targeted immunotherapies for severe COVID-19 by defining COVID-19-enriched neutrophil states and the molecular mechanisms of dexamethasone action.
New results shed light on the molecular mechanisms of dexamethasone action, underlying its therapeutic benefit in patients with severe COVID-19. 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 IFNactive 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 IFNactive 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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