TY - JOUR
KW - Cell death and immune response
KW - Influenza virus
AU - Avishekh Gautam
AU - David F. Boyd
AU - Sameer Nikhar
AU - Ting Zhang
AU - Ioannis Siokas
AU - Lee-Ann Van de Velde
AU - Jessica Gaevert
AU - Victoria Meliopoulos
AU - Bikash Thapa
AU - Diego A. Rodriguez
AU - Kathy Q. Cai
AU - Chaoran Yin
AU - Daniel Schnepf
AU - Julius Beer
AU - Carly DeAntoneo
AU - Riley M. Williams
AU - Maria Shubina
AU - Brandi Livingston
AU - Dingqiang Zhang
AU - Mark D. Andrake
AU - Seungheon Lee
AU - Raghavender Boda
AU - Anantha L. Duddupudi
AU - Jeremy Chase Crawford
AU - Peter Vogel
AU - Christian Loch
AU - Martin Schwemmle
AU - Lawrence C. Fritz
AU - Stacey Schultz-Cherry
AU - Douglas R. Green
AU - Gregory D. Cuny
AU - Paul G. Thomas
AU - Alexei Degterev
AU - Siddharth Balachandran
AB - 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.
BT - Nature
DA - 2024-04
DO - 10.1038/s41586-024-07265-8
IS - 8009
LA - en
N2 - 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.
PY - 2024
SP - 835
EP - 843
T2 - Nature
TI - Necroptosis blockade prevents lung injury in severe influenza
UR - https://www.nature.com/articles/s41586-024-07265-8
VL - 628
Y2 - 2025-08-06
SN - 1476-4687
ER -