Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation

Samuel Speaks, Matthew I. McFadden, Ashley Zani, Abigail Solstad, Steve Leumi, Jack E. Roettger, Adam D. Kenney, Hannah Bone, Lizhi Zhang, Parker J. Denz, Adrian C. Eddy, Amal O. Amer, Richard T. Robinson, Chuanxi Cai, Jianjie Ma, Emily A. Hemann, Adriana Forero () and Jacob S. Yount ()
Additional contact information
Samuel Speaks: The Ohio State University
Matthew I. McFadden: The Ohio State University
Ashley Zani: The Ohio State University
Abigail Solstad: The Ohio State University
Steve Leumi: The Ohio State University
Jack E. Roettger: The Ohio State University
Adam D. Kenney: The Ohio State University
Hannah Bone: The Ohio State University
Lizhi Zhang: The Ohio State University
Parker J. Denz: The Ohio State University
Adrian C. Eddy: The Ohio State University
Amal O. Amer: The Ohio State University
Richard T. Robinson: The Ohio State University
Chuanxi Cai: University of Virginia
Jianjie Ma: University of Virginia
Emily A. Hemann: The Ohio State University
Adriana Forero: The Ohio State University
Jacob S. Yount: The Ohio State University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Influenza virus activates cellular inflammasome pathways, which can be both beneficial and detrimental to infection outcomes. Here, we investigate the function of the inflammasome-activated, pore-forming protein gasdermin D (GSDMD) during infection. Ablation of GSDMD in knockout (KO) mice (Gsdmd−/−) significantly attenuates influenza virus-induced weight loss, lung dysfunction, lung histopathology, and mortality compared with wild type (WT) mice, despite similar viral loads. Infected Gsdmd−/− mice exhibit decreased inflammatory gene signatures shown by lung transcriptomics. Among these, diminished neutrophil gene activation signatures are corroborated by decreased detection of neutrophil elastase and myeloperoxidase in KO mouse lungs. Indeed, directly infected neutrophils are observed in vivo and infection of neutrophils in vitro induces release of DNA and tissue-damaging enzymes that is largely dependent on GSDMD. Neutrophil depletion in infected WT mice recapitulates the reductions in mortality, lung inflammation, and lung dysfunction observed in Gsdmd−/− animals, while depletion does not have additive protective effects in Gsdmd−/− mice. These findings implicate a function for GSDMD in promoting lung neutrophil responses that amplify influenza virus-induced inflammation and pathogenesis. Targeting the GSDMD/neutrophil axis may provide a therapeutic avenue for treating severe influenza.

Date: 2024
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DOI: 10.1038/s41467-024-47067-0

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