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 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.
Highlights
Abroad array of viral and bacterial infections can induce diffuse lung damage, acute respiratory distress syndrome (ARDS), respiratory failure and death[1,2,3]
Neutrophils are thought to be key drivers of ARDS4–6; neutrophil responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are still being explored. It is unclear if lung injury and ARDS observed in COVID19 share common or distinct neutrophil responses and pathways of inflammation
Dexamethasone induced the emergence of immature neutrophils expressing ARG1 and ANXA1, genes encoding immunosuppressive molecules, which were absent in healthy controls
Summary
Abroad array of viral and bacterial infections can induce diffuse lung damage, ARDS, respiratory failure and death[1,2,3]. Neutrophils are thought to be key drivers of ARDS4–6; neutrophil responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are still being explored. It is unclear if lung injury and ARDS observed in COVID19 share common or distinct neutrophil responses and pathways of inflammation. Relative to bacterial ARDS, COVID-19 was associated with preferential expansion of interferon (IFNactive) and prostaglandin (PGactive) neutrophil states. In our non-randomized, pragmatic investigation, dexamethasone in severe COVID-19 affected circulating neutrophils, altered the IFNactive state, downregulated interferon-responsive genes and activated IL-1R2+ neutrophils. Dexamethasone induced the emergence of immature neutrophils expressing ARG1 and ANXA1, genes encoding immunosuppressive molecules, which were absent in healthy controls. Dexamethasone exhibited sex-dependent effects, which might have important implications for sex-dependent outcomes and therapeutic efficacy in severe COVID-19
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