Coronavirus infection causes diffuse alveolar damage leading to acute respiratory distress syndrome. The absence of ex vivo models of human alveolar epithelium is hindering an understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here, we report a feeder-free, scalable, chemically defined, and modular alveolosphere culture system for the propagation and differentiation of human alveolar type 2 cells/pneumocytes derived from primary lung tissue. Cultured pneumocytes express the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor angiotensin-converting enzyme receptor type-2 (ACE2) and can be infected with virus. Transcriptome and histological analysis of infected alveolospheres mirror features of COVID-19 lungs, including emergence of interferon (IFN)-mediated inflammatory responses, loss of surfactant proteins, and apoptosis. Treatment of alveolospheres with IFNs recapitulates features of virus infection, including cell death. In contrast, alveolospheres pretreated with low-dose IFNs show a reduction in viral replication, suggesting the prophylactic effectiveness of IFNs against SARS-CoV-2. Human stem cell-based alveolospheres, thus, provide novel insights into COVID-19 pathogenesis and can serve as a model for understanding human respiratory diseases.

冠状病毒感染引起弥漫性肺泡损伤，导致急性呼吸窘迫综合征。没有离体人类肺泡上皮细胞模型阻碍了对 2019 年冠状病毒病 (COVID-19) 发病机制的理解。在这里，我们报告了一种无饲养层、可扩展、化学定义和模块化的肺泡培养系统，用于从原发性肺组织衍生的人类肺泡 2 型细胞/肺细胞的增殖和分化。培养的肺细胞表达严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 受体血管紧张素转换酶受体 2 型 (ACE2)，并且可以感染病毒。受感染肺泡球的转录组和组织学分析反映了 COVID-19 肺部的特征，包括出现干扰素 (IFN) 介导的炎症反应、表面活性蛋白丢失和细胞凋亡。用干扰素处理肺泡球概括了病毒感染的特征，包括细胞死亡。相比之下，用低剂量 IFN 预处理的肺泡球显示出病毒复制减少，这表明 IFN 对 SARS-CoV-2 具有预防作用。因此，基于人类干细胞的肺泡球为 COVID-19 发病机制提供了新的见解，并可作为了解人类呼吸系统疾病的模型。