Programmed cell death is a pivotal mechanism of cell-autonomous immune defense against viral infections. Recent studies indicate that both blocking and promoting cell death negatively affect coronavirus replication, implying that coronaviruses may fine-tune cell death pathways to optimize their propagation. However, the mechanisms underlying this remain poorly understood. Here, it is verified that coronaviruses induce the formation of a Z-DNA-binding protein 1 (ZBP1)-initiated cell death complex involving ZBP1, Z-RNA, receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and caspase-8, thereby triggering apoptosis, pyroptosis, and necroptosis in human bronchial epithelial cells. To impede the activati... More
Programmed cell death is a pivotal mechanism of cell-autonomous immune defense against viral infections. Recent studies indicate that both blocking and promoting cell death negatively affect coronavirus replication, implying that coronaviruses may fine-tune cell death pathways to optimize their propagation. However, the mechanisms underlying this remain poorly understood. Here, it is verified that coronaviruses induce the formation of a Z-DNA-binding protein 1 (ZBP1)-initiated cell death complex involving ZBP1, Z-RNA, receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and caspase-8, thereby triggering apoptosis, pyroptosis, and necroptosis in human bronchial epithelial cells. To impede the activation of apoptosis and pyroptosis, NSP5 and ORF6 of SARS-CoV-2 concurrently inhibit caspase-8 activity by targeting its large and small subunits, respectively. Additionally, NSP13, the viral helicase, interacts with RIPK3 to impair its binding to ZBP1, thus suppressing ZBP1-initiated necroptosis. This inhibitory effect on cell death is likely conserved across β-coronaviruses. Furthermore, co-infection of influenza A virus and SARS-CoV-2 is demonstrated to exacerbate disease severity, although the mechanisms remain unclear. These findings suggest that β-coronavirus-induced inhibition of cell death enhances influenza A virus replication and worsens inflammation during their co-infection, ultimately increasing mortality in mice. This research provides valuable insights into the regulation of coronavirus-induced cell death, offering potential therapeutic strategies for combating highly pathogenic coronavirus infections.
