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^active 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^active 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.

尽管对宿主防御至关重要，但先天免疫细胞也是急性呼吸窘迫综合征 (ARDS) 的病理驱动因素。与其他呼吸道病原体引起的 ARDS 相比，2019 年冠状病毒病 (COVID-19) ARDS 期间的先天免疫动力学尚不清楚。此外，地塞米松在严重 COVID-19 期间产生有益作用的潜在机制仍然难以捉摸。使用单细胞 RNA 测序和血浆蛋白质组学，我们发现，与细菌性 ARDS 相比，COVID-19 与以干扰素 (IFN) 和前列腺素信号传导为特征的不同中性粒细胞状态的扩展有关。严重 COVID-19 期间的地塞米松影响循环中性粒细胞，改变 IFN^活性中性粒细胞，下调干扰素刺激基因并激活 IL-1R2 ⁺中性粒细胞。地塞米松还通过将中性粒细胞从信息接收者转变为信息提供者来扩大免疫抑制性未成熟中性粒细胞并重塑细胞相互作用。男性患者有较高比例的 IFN^活性中性粒细胞和优先类固醇诱导的未成熟中性粒细胞扩张，可能影响结果。我们的单细胞图谱（参见“数据可用性”部分）定义了富含 COVID-19 的中性粒细胞状态和地塞米松作用的分子机制，以开发针对严重 COVID-19 的靶向免疫疗法。