Necroptosis blockade prevents lung injury in severe influenza

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

doi:10.1038/s41586-024-07265-8

Necroptosis blockade prevents lung injury in severe influenza

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. AndrakeSeungheon 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

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	835-843
Number of pages	9
Journal	Nature
Volume	628
Issue number	8009
DOIs	https://doi.org/10.1038/s41586-024-07265-8
State	Published - Mar 2024

Keywords

Alveolar Epithelial Cells/pathology
Animals
Female
Humans
Influenza A virus/physiology
Influenza, Human/virology
Lung Injury/prevention & control
Male
Mice
Mice, Inbred C57BL
Necroptosis/drug effects
Orthomyxoviridae Infections/drug therapy
Protein Kinase Inhibitors/pharmacology
Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
Respiratory Distress Syndrome/virology

Access to Document

10.1038/s41586-024-07265-8

Cite this

Gautam, A., Boyd, D. F., Nikhar, S., Zhang, T., Siokas, I., Van de Velde, L. A., Gaevert, J., Meliopoulos, V., Thapa, B., Rodriguez, D. A., Cai, K. Q., Yin, C., Schnepf, D., Beer, J., DeAntoneo, C., Williams, R. M., Shubina, M., Livingston, B., Zhang, D., ... Balachandran, S. (2024). Necroptosis blockade prevents lung injury in severe influenza. Nature, 628(8009), 835-843. https://doi.org/10.1038/s41586-024-07265-8

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title = "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.",

keywords = "Alveolar Epithelial Cells/pathology, Animals, Female, Humans, Influenza A virus/physiology, Influenza, Human/virology, Lung Injury/prevention & control, Male, Mice, Mice, Inbred C57BL, Necroptosis/drug effects, Orthomyxoviridae Infections/drug therapy, Protein Kinase Inhibitors/pharmacology, Receptor-Interacting Protein Serine-Threonine Kinases/metabolism, Respiratory Distress Syndrome/virology",

author = "Avishekh Gautam and Boyd, {David F.} and Sameer Nikhar and Ting Zhang and Ioannis Siokas and {Van de Velde}, {Lee Ann} and Jessica Gaevert and Victoria Meliopoulos and Bikash Thapa and Rodriguez, {Diego A.} and Cai, {Kathy Q.} and Chaoran Yin and Daniel Schnepf and Julius Beer and Carly DeAntoneo and Williams, {Riley M.} and Maria Shubina and Brandi Livingston and Dingqiang Zhang and Andrake, {Mark D.} and Seungheon Lee and Raghavender Boda and Duddupudi, {Anantha L.} and Crawford, {Jeremy Chase} and Peter Vogel and Christian Loch and Martin Schwemmle and Fritz, {Lawrence C.} and Stacey Schultz-Cherry and Green, {Douglas R.} and Cuny, {Gregory D.} and Thomas, {Paul G.} and Alexei Degterev and Siddharth Balachandran",

note = "{\textcopyright} 2024. The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2024",

month = mar,

doi = "10.1038/s41586-024-07265-8",

language = "English",

volume = "628",

pages = "835--843",

journal = "Nature",

issn = "0028-0836",

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Gautam, A, Boyd, DF, Nikhar, S, Zhang, T, Siokas, I, Van de Velde, LA, Gaevert, J, Meliopoulos, V, Thapa, B, Rodriguez, DA, Cai, KQ, Yin, C, Schnepf, D, Beer, J, DeAntoneo, C, Williams, RM, Shubina, M, Livingston, B, Zhang, D, Andrake, MD, Lee, S, Boda, R, Duddupudi, AL, Crawford, JC, Vogel, P, Loch, C, Schwemmle, M, Fritz, LC, Schultz-Cherry, S, Green, DR, Cuny, GD, Thomas, PG, Degterev, A & Balachandran, S 2024, 'Necroptosis blockade prevents lung injury in severe influenza', Nature, vol. 628, no. 8009, pp. 835-843. https://doi.org/10.1038/s41586-024-07265-8

TY - JOUR

T1 - Necroptosis blockade prevents lung injury in severe influenza

AU - Gautam, Avishekh

AU - Boyd, David F.

AU - Nikhar, Sameer

AU - Zhang, Ting

AU - Siokas, Ioannis

AU - Van de Velde, Lee Ann

AU - Gaevert, Jessica

AU - Meliopoulos, Victoria

AU - Thapa, Bikash

AU - Rodriguez, Diego A.

AU - Cai, Kathy Q.

AU - Yin, Chaoran

AU - Schnepf, Daniel

AU - Beer, Julius

AU - DeAntoneo, Carly

AU - Williams, Riley M.

AU - Shubina, Maria

AU - Livingston, Brandi

AU - Zhang, Dingqiang

AU - Andrake, Mark D.

AU - Lee, Seungheon

AU - Boda, Raghavender

AU - Duddupudi, Anantha L.

AU - Crawford, Jeremy Chase

AU - Vogel, Peter

AU - Loch, Christian

AU - Schwemmle, Martin

AU - Fritz, Lawrence C.

AU - Schultz-Cherry, Stacey

AU - Green, Douglas R.

AU - Cuny, Gregory D.

AU - Thomas, Paul G.

AU - Degterev, Alexei

AU - Balachandran, Siddharth

PY - 2024/3

Y1 - 2024/3

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.

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.

KW - Alveolar Epithelial Cells/pathology

KW - Animals

KW - Female

KW - Humans

KW - Influenza A virus/physiology

KW - Influenza, Human/virology

KW - Lung Injury/prevention & control

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Necroptosis/drug effects

KW - Orthomyxoviridae Infections/drug therapy

KW - Protein Kinase Inhibitors/pharmacology

KW - Receptor-Interacting Protein Serine-Threonine Kinases/metabolism

KW - Respiratory Distress Syndrome/virology

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U2 - 10.1038/s41586-024-07265-8

DO - 10.1038/s41586-024-07265-8

M3 - Article

C2 - 38600381

AN - SCOPUS:85189948885

SN - 0028-0836

VL - 628

SP - 835

EP - 843

JO - Nature

JF - Nature

IS - 8009

ER -

Necroptosis blockade prevents lung injury in severe influenza

Abstract

Keywords

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Cite this

Necroptosis blockade prevents lung injury in severe influenza

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Press/Media

New Influenza A Virus Study Findings Have Been Reported by Investigators at Fox Chase Cancer Center (Necroptosis Blockade Prevents Lung Injury In Severe Influenza)

Researchers create novel drug that can prevent flu-induced lung injury

Serious flu damage prevented by compound that blocks unnecessary cell death

Cite this