Necroptosis blockade prevents lung injury in severe influenza.

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.

• Authors: Avishekh Gautam, David F Boyd, Sameer Nikhar, Ting Zhang, Ioannis Siokas, Lee-Ann Van de 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, Siddharth Balachandran
• Journal: Nature (Nature) Vol. 628 Issue 8009 Pg. 835-843 (Apr 2024) ISSN: 1476-4687 [Electronic] England
• PMID: 38600381 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2024. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Protein Kinase Inhibitors
• Receptor-Interacting Protein Serine-Threonine Kinases
• RIPK3 protein, human
• Ripk3 protein, mouse

Topics

• Animals
• Female
• Humans
• Male
• Mice
• Alveolar Epithelial Cells (pathology, drug effects, virology, metabolism)
• Influenza A virus (classification, drug effects, immunology, pathogenicity)
• Lung Injury (complications, pathology, prevention & control, virology)
• Mice, Inbred C57BL
• Necroptosis (drug effects)
• Orthomyxoviridae Infections (complications, drug therapy, immunology, mortality, virology)
• Protein Kinase Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism, antagonists & inhibitors)
• Respiratory Distress Syndrome (complications, pathology, prevention & control, virology)