Necroptosis blockade prevents lung injury in severe influenza

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, Daniel Schnepf, Julius Beer, Carly DeAntoneo, Riley M. Williams, Maria Shubina, Brandi Livingston, Dingqiang Zhang, Mark D. Andrake, Seungheon Lee, Raghavender Boda, Anantha L. Duddupudi, Jeremy Chase Crawford, Peter Vogel, Christian Loch, Martin Schwemmle, Lawrence C. Fritz, Stacey Schultz-Cherry, Douglas R. Green, Gregory D. Cuny (), Paul G. Thomas (), Alexei Degterev () and Siddharth Balachandran ()
Additional contact information
Avishekh Gautam: Fox Chase Cancer Center
David F. Boyd: St Jude Children’s Research Hospital
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
Alexei Degterev: Tufts University School of Medicine
Siddharth Balachandran: Fox Chase Cancer Center

Nature, 2024, vol. 628, issue 8009, 835-843

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07265-8

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