ZBP1-driven cell death in severe influenza.

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Influenza A virus (IAV) infection can lead to severe human illness, with high virus replication in lower respiratory tract alveoli driving disease severity.
• Lytic death of infected alveolar epithelial cells (AECs) is a key factor in severe influenza pathogenesis.
• Programmed cell death (PCD) pathways, including apoptosis, necroptosis, and pyroptosis, are implicated in IAV-induced pathology.

Purpose of the Study:

• To investigate the role of Z-form nucleic-acid-binding protein 1 (ZBP1) in IAV-induced programmed cell death (PCD).
• To explore the therapeutic potential of targeting ZBP1-mediated necroinflammatory cell lysis in severe influenza.

Main Methods:

• Studies involved analyzing molecular mechanisms of IAV-induced lytic cell death.
• Investigated ZBP1's role in sensing replicating IAV and initiating PCD pathways.
• Evaluated pharmacological blockade of necroptosis in mouse models of lethal influenza.

Main Results:

• ZBP1 senses replicating IAV, triggering PCD including apoptosis and necroptosis in AECs, and pyroptosis in myeloid cells.
• Necroptosis and pyroptosis, both lytic cell death forms, significantly contribute to pathogenesis during severe influenza infections.
• Pharmacological inhibition of necroptosis demonstrated significant therapeutic potential in preclinical models of lethal influenza.

Conclusions:

• ZBP1-initiated necroinflammatory cell lysis is a critical mechanism in severe influenza pathogenesis.
• Targeting ZBP1-mediated cell lysis, potentially combined with antiviral drugs, represents a promising clinical strategy for treating severe influenza.