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Nature
. 2024 Apr 10.
doi: 10.1038/s41586-024-07265-8. Online ahead of print. Necroptosis blockade prevents lung injury in severe influenza
Avishekh Gautam # 1 , David F Boyd # 2 3 4 , Sameer Nikhar 5 , Ting Zhang 1 , Ioannis Siokas 6 , Lee-Ann Van de Velde 3 , Jessica Gaevert 3 , Victoria Meliopoulos 3 , Bikash Thapa 1 , Diego A Rodriguez 2 , Kathy Q Cai 1 , Chaoran Yin 1 , Daniel Schnepf 7 , Julius Beer 7 , Carly DeAntoneo 1 , Riley M Williams 1 , Maria Shubina 1 , Brandi Livingston 3 , Dingqiang Zhang 6 , Mark D Andrake 1 , Seungheon Lee 5 , Raghavender Boda 5 , Anantha L Duddupudi 5 , Jeremy Chase Crawford 3 , Peter Vogel 8 , Christian Loch 9 , Martin Schwemmle 7 , Lawrence C Fritz 10 , Stacey Schultz-Cherry 3 , Douglas R Green 2 , Gregory D Cuny 11 , Paul G Thomas 12 13 , Alexei Degterev 14 , Siddharth Balachandran 15
Affiliations
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.
. 2024 Apr 10.
doi: 10.1038/s41586-024-07265-8. Online ahead of print. Necroptosis blockade prevents lung injury in severe influenza
Avishekh Gautam # 1 , David F Boyd # 2 3 4 , Sameer Nikhar 5 , Ting Zhang 1 , Ioannis Siokas 6 , Lee-Ann Van de Velde 3 , Jessica Gaevert 3 , Victoria Meliopoulos 3 , Bikash Thapa 1 , Diego A Rodriguez 2 , Kathy Q Cai 1 , Chaoran Yin 1 , Daniel Schnepf 7 , Julius Beer 7 , Carly DeAntoneo 1 , Riley M Williams 1 , Maria Shubina 1 , Brandi Livingston 3 , Dingqiang Zhang 6 , Mark D Andrake 1 , Seungheon Lee 5 , Raghavender Boda 5 , Anantha L Duddupudi 5 , Jeremy Chase Crawford 3 , Peter Vogel 8 , Christian Loch 9 , Martin Schwemmle 7 , Lawrence C Fritz 10 , Stacey Schultz-Cherry 3 , Douglas R Green 2 , Gregory D Cuny 11 , Paul G Thomas 12 13 , Alexei Degterev 14 , Siddharth Balachandran 15
Affiliations
- PMID: 38600381
- DOI: 10.1038/s41586-024-07265-8
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.
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