Abstract：
Virus-induced cell death is a key contributor to COVID-19 pathology. Cell death induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well studied in myeloid cells but less in its primary host cell type, angiotensin-converting enzyme 2 (ACE2)-expressing human airway epithelia (HAE). SARS-CoV-2 induces apoptosis, necroptosis, and pyroptosis in HAE organotypic cultures. Single-cell and limiting-dilution analysis revealed that necroptosis is the primary cell death event in infected cells, whereas uninfected bystanders undergo apoptosis, and pyroptosis occurs later during infection. Mechanistically, necroptosis is induced by viral Z-RNA binding to Z-DNA-binding protein 1 (ZBP1) in HAE and lung tissues from patients with COVID-19. The Delta (B.1.617.2) variant, which causes more severe disease than Omicron (B1.1.529) in humans, is associated with orders of magnitude-greater Z-RNA/ZBP1 interactions, necroptosis, and disease severity in animal models. Thus, Delta induces robust ZBP1-mediated necroptosis and more disease severity.
摘要：
病毒诱导的细胞死亡是COVID-19病理的关键因素。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）诱导的细胞死亡在骨髓细胞中得到了很好的研究，但在其原代宿主细胞类型中研究较少。表达血管紧张素转换酶2（ACE2）的人气道上皮（HAE）。SARS-CoV-2诱导细胞凋亡,坏死,HAE器官型培养中的焦亡。单细胞和有限稀释分析显示，坏死是感染细胞的主要细胞死亡事件，而未感染的旁观者经历细胞凋亡，和焦亡发生在感染的后期。机械上,在COVID-19患者的HAE和肺组织中，病毒Z-RNA与Z-DNA结合蛋白1（ZBP1）的结合诱导坏死。Delta(B.1.617.2)变种，在人类中导致比Omicron（B1.1.529）更严重的疾病，与更大数量级的Z-RNA/ZBP1相互作用相关，坏死,和动物模型中的疾病严重程度。因此，Delta诱导强烈的ZBP1介导的坏死和更严重的疾病。
