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Necroptosis blockade prevents lung injury in severe influenza

Author

Listed:
  • Avishekh Gautam

    (Fox Chase Cancer Center)

  • David F. Boyd

    (St Jude Children’s Research Hospital
    St Jude Children’s Research Hospital
    University of California)

  • Sameer Nikhar

    (University of Houston)

  • Ting Zhang

    (Fox Chase Cancer Center)

  • Ioannis Siokas

    (Tufts University School of Medicine)

  • Lee-Ann Velde

    (St Jude Children’s Research Hospital)

  • Jessica Gaevert

    (St Jude Children’s Research Hospital)

  • Victoria Meliopoulos

    (St Jude Children’s Research Hospital)

  • Bikash Thapa

    (Fox Chase Cancer Center)

  • Diego A. Rodriguez

    (St Jude Children’s Research Hospital)

  • Kathy Q. Cai

    (Fox Chase Cancer Center)

  • Chaoran Yin

    (Fox Chase Cancer Center)

  • Daniel Schnepf

    (University of Freiburg)

  • Julius Beer

    (University of Freiburg)

  • Carly DeAntoneo

    (Fox Chase Cancer Center)

  • Riley M. Williams

    (Fox Chase Cancer Center)

  • Maria Shubina

    (Fox Chase Cancer Center)

  • Brandi Livingston

    (St Jude Children’s Research Hospital)

  • Dingqiang Zhang

    (Tufts University School of Medicine)

  • Mark D. Andrake

    (Fox Chase Cancer Center)

  • Seungheon Lee

    (University of Houston)

  • Raghavender Boda

    (University of Houston)

  • Anantha L. Duddupudi

    (University of Houston)

  • Jeremy Chase Crawford

    (St Jude Children’s Research Hospital)

  • Peter Vogel

    (St. Jude Children’s Research Hospital)

  • Christian Loch

    (Reaction Biology)

  • Martin Schwemmle

    (University of Freiburg)

  • Lawrence C. Fritz

    (Vaayu Therapeutics)

  • Stacey Schultz-Cherry

    (St Jude Children’s Research Hospital)

  • Douglas R. Green

    (St Jude Children’s Research Hospital)

  • Gregory D. Cuny

    (University of Houston)

  • Paul G. Thomas

    (St Jude Children’s Research Hospital
    St Jude Children’s Research Hospital)

  • Alexei Degterev

    (Tufts University School of Medicine)

  • Siddharth Balachandran

    (Fox Chase Cancer Center)

Abstract

Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1–5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6–8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.

Suggested Citation

  • Avishekh Gautam & David F. Boyd & Sameer Nikhar & Ting Zhang & Ioannis Siokas & Lee-Ann Velde & Jessica Gaevert & Victoria Meliopoulos & Bikash Thapa & Diego A. Rodriguez & Kathy Q. Cai & Chaoran Yin , 2024. "Necroptosis blockade prevents lung injury in severe influenza," Nature, Nature, vol. 628(8009), pages 835-843, April.
    • Handle: RePEc:nat:nature:v:628:y:2024:i:8009:d:10.1038_s41586-024-07265-8
    DOI: 10.1038/s41586-024-07265-8
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