Necroptosis blockade prevents lung injury in severe influenza.

Autor: Gautam A; Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA., Boyd DF; Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.; Department of Host-Microbe Interactions, St Jude Children's Research Hospital, Memphis, TN, USA.; Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, USA., Nikhar S; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA., Zhang T; Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA., Siokas I; Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA., Van de Velde LA; Department of Host-Microbe Interactions, St Jude Children's Research Hospital, Memphis, TN, USA., Gaevert J; Department of Host-Microbe Interactions, St Jude Children's Research Hospital, Memphis, TN, USA., Meliopoulos V; Department of Host-Microbe Interactions, St Jude Children's Research Hospital, Memphis, TN, USA., Thapa B; Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA., Rodriguez DA; Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA., Cai KQ; Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA., Yin C; Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA., Schnepf D; Institute of Virology Department for Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Beer J; Institute of Virology Department for Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany., DeAntoneo C; Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA., Williams RM; Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA., Shubina M; Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA., Livingston B; Department of Host-Microbe Interactions, St Jude Children's Research Hospital, Memphis, TN, USA., Zhang D; Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA., Andrake MD; Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA., Lee S; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA., Boda R; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA., Duddupudi AL; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA., Crawford JC; Department of Host-Microbe Interactions, St Jude Children's Research Hospital, Memphis, TN, USA., Vogel P; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Loch C; Reaction Biology, Malvern, PA, USA., Schwemmle M; Institute of Virology Department for Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Fritz LC; Vaayu Therapeutics, Rancho Santa Fe, CA, USA., Schultz-Cherry S; Department of Host-Microbe Interactions, St Jude Children's Research Hospital, Memphis, TN, USA., Green DR; Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA., Cuny GD; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA. gdcuny@central.uh.edu., Thomas PG; Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. paul.thomas@stjude.org.; Department of Host-Microbe Interactions, St Jude Children's Research Hospital, Memphis, TN, USA. paul.thomas@stjude.org., Degterev A; Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA. alexei.degterev@tufts.edu., Balachandran S; Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA. Siddharth.balachandran@fccc.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Apr; Vol. 628 (8009), pp. 835-843. Date of Electronic Publication: 2024 Apr 10.
DOI: 10.1038/s41586-024-07265-8
Abstrakt: Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome 1-5 (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 infection 6-8 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. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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