The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating pandemic. Although most people infected with SARS-CoV-2 develop a mild to moderate disease with virus replication restricted mainly to the upper airways, some progress to having a life-threatening pneumonia. In this Review, we explore recent clinical and experimental advances regarding SARS-CoV-2 pathophysiology and discuss potential mechanisms behind SARS-CoV-2-associated acute respiratory distress syndrome (ARDS), specifically focusing on new insights obtained using novel technologies such as single-cell omics, organoid infection models and CRISPR screens. We describe how SARS-CoV-2 may infect the lower respiratory tract and cause alveolar damage as a result of dysfunctional immune responses. We discuss how this may lead to the induction of a ‘leaky state’ of both the epithelium and the endothelium, promoting inflammation and coagulation, while an influx of immune cells leads to overexuberant inflammatory responses and immunopathology. Finally, we highlight how these findings may aid the development of new therapeutic interventions against COVID-19.

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的出现已造成毁灭性的大流行。尽管大多数感染 SARS-CoV-2 的人会发展为轻度至中度疾病，病毒复制主要局限于上呼吸道，但有些人会发展为危及生命的肺炎。在这篇综述中，我们探讨了有关 SARS-CoV-2 病理生理学的最新临床和实验进展，并讨论了 SARS-CoV-2 相关急性呼吸窘迫综合征 (ARDS) 背后的潜在机制，特别关注使用新技术获得的新见解，例如单一-细胞组学、类器官感染模型和 CRISPR 筛选。我们描述了 SARS-CoV-2 如何感染下呼吸道并由于免疫反应功能失调而导致肺泡损伤。我们讨论了这可能如何导致上皮细胞和内皮细胞的“渗漏状态”的诱导，从而促进炎症和凝血，而免疫细胞的涌入导致过度的炎症反应和免疫病理学。最后，我们强调了这些发现如何有助于开发针对 COVID-19 的新治疗干预措施。