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

While critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during COVID-19 ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using scRNA-seq and plasma proteomics, we discovered that compared to bacterial ARDS, COVID-19 was associated with distinct neutrophil polarization characterized by interferon (IFN) and prostaglandin (PG) active states. Dexamethasone during severe COVID-19 depleted circulating neutrophils, altered IFN^active neutrophils, downregulated interferon-stimulated gene, and activated IL1R2^+ve neutrophils. Dexamethasone also expanded immature neutrophils expressing immunosuppressive molecules and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFN^active neutrophils, preferential steroid-induced immature neutrophil expansion, and possibly different effects on outcome. Our single-cell atlas (www.biernaskielab.ca/COVID_neutrophil) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.<br>