Gasdermin E deficiency limits inflammation and lung damage during influenza virus infection
Abstract 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 t...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-06-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07748-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849724801842675712 |
|---|---|
| author | Sarah Rosli Rebecca L. Ambrose Christopher M. Harpur Maggie Lam Christopher Hodges Kristian T. Barry Alison C. West Ashley Mansell Kate E. Lawlor Michelle D. Tate |
| author_facet | Sarah Rosli Rebecca L. Ambrose Christopher M. Harpur Maggie Lam Christopher Hodges Kristian T. Barry Alison C. West Ashley Mansell Kate E. Lawlor Michelle D. Tate |
| author_sort | Sarah Rosli |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-e3f4530673264d0890b17dfbfbb716c0 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-e3f4530673264d0890b17dfbfbb716c02025-08-20T03:10:38ZengNature Publishing GroupCell Death and Disease2041-48892025-06-0116111310.1038/s41419-025-07748-0Gasdermin E deficiency limits inflammation and lung damage during influenza virus infectionSarah Rosli0Rebecca L. Ambrose1Christopher M. Harpur2Maggie Lam3Christopher Hodges4Kristian T. Barry5Alison C. West6Ashley Mansell7Kate E. Lawlor8Michelle D. Tate9Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchAbstract 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.https://doi.org/10.1038/s41419-025-07748-0 |
| spellingShingle | Sarah Rosli Rebecca L. Ambrose Christopher M. Harpur Maggie Lam Christopher Hodges Kristian T. Barry Alison C. West Ashley Mansell Kate E. Lawlor Michelle D. Tate Gasdermin E deficiency limits inflammation and lung damage during influenza virus infection Cell Death and Disease |
| title | Gasdermin E deficiency limits inflammation and lung damage during influenza virus infection |
| title_full | Gasdermin E deficiency limits inflammation and lung damage during influenza virus infection |
| title_fullStr | Gasdermin E deficiency limits inflammation and lung damage during influenza virus infection |
| title_full_unstemmed | Gasdermin E deficiency limits inflammation and lung damage during influenza virus infection |
| title_short | Gasdermin E deficiency limits inflammation and lung damage during influenza virus infection |
| title_sort | gasdermin e deficiency limits inflammation and lung damage during influenza virus infection |
| url | https://doi.org/10.1038/s41419-025-07748-0 |
| work_keys_str_mv | AT sarahrosli gasderminedeficiencylimitsinflammationandlungdamageduringinfluenzavirusinfection AT rebeccalambrose gasderminedeficiencylimitsinflammationandlungdamageduringinfluenzavirusinfection AT christophermharpur gasderminedeficiencylimitsinflammationandlungdamageduringinfluenzavirusinfection AT maggielam gasderminedeficiencylimitsinflammationandlungdamageduringinfluenzavirusinfection AT christopherhodges gasderminedeficiencylimitsinflammationandlungdamageduringinfluenzavirusinfection AT kristiantbarry gasderminedeficiencylimitsinflammationandlungdamageduringinfluenzavirusinfection AT alisoncwest gasderminedeficiencylimitsinflammationandlungdamageduringinfluenzavirusinfection AT ashleymansell gasderminedeficiencylimitsinflammationandlungdamageduringinfluenzavirusinfection AT kateelawlor gasderminedeficiencylimitsinflammationandlungdamageduringinfluenzavirusinfection AT michelledtate gasderminedeficiencylimitsinflammationandlungdamageduringinfluenzavirusinfection |