Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome¹ (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia². Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.

一些感染严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的患者会发展为严重肺炎和急性呼吸窘迫综合征¹ (ARDS)。这些患者的不同临床特征导致人们猜测，感染 SARS-CoV-2 的肺泡对病毒的免疫反应不同于其他类型肺炎². 在这里，我们通过表征感染该病毒的患者肺泡中的免疫反应来研究 SARS-CoV-2 的病理生物学。我们收集了 88 名 SARS-CoV-2 引起的呼吸衰竭患者和 211 名已知或疑似其他病原体肺炎患者的支气管肺泡灌洗液样本，并使用流式细胞术和批量转录组学分析对它们进行了分析。我们对插管后 48 小时内从 2019 年严重冠状病毒病 (COVID-19) 患者采集的 10 份支气管肺泡灌洗液样本进行了单细胞 RNA 测序。在大多数 SARS-CoV-2 感染患者中，肺泡腔持续富含 T 细胞和单核细胞。大量和单细胞转录组学分析表明 SARS-CoV-2 感染肺泡巨噬细胞，反过来通过产生 T 细胞化学引诱剂做出反应。这些 T 细胞产生干扰素-γ 以诱导肺泡巨噬细胞释放炎性细胞因子并进一步促进 T 细胞活化。总的来说，我们的研究结果表明，SARS-CoV-2 会导致缓慢展开、空间受限的肺泡炎，其中含有 SARS-CoV-2 和 T 细胞的肺泡巨噬细胞形成一个正反馈回路，驱动持续性肺泡炎症。