Necroptosis Blockade Prevents Lung Injury in Severe Influenza

Overview

Journal Nature

Specialty Science

Date 2024 Apr 10

PMID 38600381

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

Affiliations

Soon will be listed here.

Abstract

Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome (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 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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