Initiator cell death event induced by SARS-CoV- 2 in the human airway epithelium

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

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