Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Influenza A virus (IAV) infection triggers programmed cell death pathways, including apoptosis and necroptosis.
• Z-uric acid-binding protein 1 (ZBP1) senses viral RNA and activates RIPK3-mediated cell death.
• Mixed lineage kinase domain-like pseudokinase (MLKL) is a key effector in necroptosis.

Purpose of the Study:

• To investigate the role of ZBP1 and MLKL in IAV-induced cell death.
• To identify the specific viral components that activate ZBP1 during IAV infection.
• To elucidate the consequences of nuclear MLKL activation in the context of IAV pathogenesis.

Main Methods:

• Utilized cell culture and mouse models of IAV infection.
• Employed molecular biology techniques to detect Z-RNAs and assess ZBP1 activation.
• Analyzed cell death pathways, nuclear envelope integrity, and neutrophil recruitment.

Main Results:

• Replicating IAV generates Z-RNAs that activate ZBP1 within the nucleus.
• Nuclear ZBP1 activation leads to RIPK3-mediated MLKL activation, nuclear envelope disruption, and necroptosis.
• MLKL-deficient mice exhibited reduced lung pathology, decreased neutrophil infiltration, and improved survival after lethal IAV challenge.
• Nuclear MLKL activation strongly promoted neutrophil activation, a key driver of influenza-associated inflammation.

Conclusions:

• Z-RNA is identified as a novel pathogen-associated molecular pattern (PAMP) that activates ZBP1.
• A ZBP1-initiated "inside-out" cell death pathway originating in the nucleus is described.
• This pathway contributes to inflammatory pathology in severe influenza, suggesting therapeutic potential.