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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. Editor's summary: SARS-CoV-2 infection triggers multiple cell death pathways that contribute to disease severity. Here, Liang et al. characterized cell death mechanisms in angiotensin-converting enzyme 2 (ACE2)–expressing cells and primary human airway epithelial (HAE) cell cultures during SARS-CoV-2 infection and in autopsied lungs from patients with COVID-19. Necroptosis was the primary form of cell death and was induced by viral Z-RNA binding to Z-DNA binding protein-1 (ZBP-1). Infected and bystander cells underwent apoptosis, but limiting dilution analysis showed that apoptosis was a bystander effect. The Delta variant induced much greater Z-RNA/ZBP-1 interactions and necroptosis compared with Omicron, thus suggesting a mechanism associated with greater disease severity (see related Focus by Wong and Perlman). —Christiana N. Fogg [ABSTRACT FROM AUTHOR]