Gasdermin E deficiency limits inflammation and lung damage during influenza virus infection

Severe influenza A virus (IAV) infections are associated with hyperinflammation and significant lung damage. Gasdermin E (GSDME) mediates pyroptosis, a lytic and inflammatory type of cell death. Cleavage of GSDME by caspase-3 releases the active N-terminal domain, which subsequently forms transmembr...

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Bibliographic Details
Published in:Cell death & disease Vol. 16; no. 1; pp. 440 - 13
Main Authors: Rosli, Sarah, Ambrose, Rebecca L., Harpur, Christopher M., Lam, Maggie, Hodges, Christopher, Barry, Kristian T., West, Alison C., Mansell, Ashley, Lawlor, Kate E., Tate, Michelle D.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 06.06.2025
Springer Nature B.V
Nature Publishing Group
Subjects:
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14/19
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82/51
82/80
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96/106
96/31
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Animals
Antibodies
Biochemistry
Biomedical and Life Sciences
Caspase 3 - metabolism
Caspase-3
Cell Biology
Cell Culture
Cell death
Disease resistance
E-cadherin
Epithelial cells
Epithelial Cells - metabolism
Epithelial Cells - pathology
Epithelial Cells - virology
Gasdermins
Humans
Immunology
Infections
Inflammation - pathology
Influenza
Influenza A
Influenza A virus - pathogenicity
Influenza, Human - pathology
Influenza, Human - virology
Interleukin 6
Leukocytes (neutrophilic)
Life Sciences
Lung - metabolism
Lung - pathology
Lung - virology
Mice
Mice, Inbred C57BL
Mice, Knockout
Orthomyxoviridae Infections - genetics
Orthomyxoviridae Infections - metabolism
Orthomyxoviridae Infections - pathology
Orthomyxoviridae Infections - virology
Pathogenesis
Phosphate-Binding Proteins - deficiency
Pyroptosis
siRNA
γ-Interferon
ISSN:2041-4889, 2041-4889
Online Access:Get full text
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Summary:Severe influenza A virus (IAV) infections are associated with hyperinflammation and significant lung damage. Gasdermin E (GSDME) mediates pyroptosis, a lytic and inflammatory type of cell death. Cleavage of GSDME by caspase-3 releases the active N-terminal domain, which subsequently forms transmembrane pores, leading to cell lysis and death. In this study, we investigated a role for GSDME in severe influenza. Infection of human bronchial epithelial cells revealed that IAV induces GSDME cleavage and activation, with the magnitude and kinetics of GSDME activation differing between IAV strains. Caspase-3-mediated GSDME activation preceded and overwhelmed gasdermin D (GSDMD) activation. siRNA silencing in vitro confirmed both gasdermins are active in human bronchial epithelial cells and cooperate to drive IAV responses. IAV infection of mice promoted GSDME cleavage in E-cadherin + epithelial cells in vivo at day 3. Mice deficient in GSDME ( Gsdme −/− ) showed improved survival and greater influenza disease resistance compared to their wildtype littermate controls. Gsdme −/− mice exhibited reduced neutrophil infiltration and levels of cytokines IL-6 and IL-1β in the airways and IL-6, TNF, and IFNγ in the serum. This was accompanied by reduced viral loads, lung pathology, and epithelial cell death. Together, these findings demonstrate a pivotal role for GSDME in severe influenza pathogenesis.
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ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-025-07748-0