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Title: Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention

Abstract

Influenza is a worldwide health and financial burden posing a significant risk to the immune-compromised, obese, diabetic, elderly, and pediatric populations. We identified increases in glucose metabolism in the lungs of pediatric patients infected with respiratory pathogens. Using quantitative mass spectrometry, we found metabolic changes occurring after influenza infection in primary human respiratory cells and validated infection-associated increases in c-Myc, glycolysis, and glutaminolysis. We confirmed these findings with a metabolic drug screen that identified the PI3K/mTOR inhibitor BEZ235 as a regulator of infectious virus production. BEZ235 treatment ablated the transient induction of c-Myc, restored PI3K/mTOR pathway homeostasis measured by 4E-BP1 and p85 phosphorylation, and reversed infection-induced changes in metabolism. Importantly, BEZ235 reduced infectious progeny but had no effect on the early stages of viral replication. BEZ235 significantly increased survival in mice, while reducing viral titer. We show metabolic reprogramming of host cells by influenza virus exposes targets for therapeutic intervention.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1377984
Alternate Identifier(s):
OSTI ID: 1364393
Grant/Contract Number:  
AC05-76RL0 1830; AC0576RL01830
Resource Type:
Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Name: Cell Reports Journal Volume: 19 Journal Issue: 8; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
Netherlands
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Smallwood, Heather S., Duan, Susu, Morfouace, Marie, Rezinciuc, Svetlana, Shulkin, Barry L., Shelat, Anang, Zink, Erika E., Milasta, Sandra, Bajracharya, Resha, Oluwaseum, Ajayi J., Roussel, Martine F., Green, Douglas R., Pasa-Tolic, Ljiljana, and Thomas, Paul G.. Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention. Netherlands: N. p., 2017. Web. https://doi.org/10.1016/j.celrep.2017.04.039.
Smallwood, Heather S., Duan, Susu, Morfouace, Marie, Rezinciuc, Svetlana, Shulkin, Barry L., Shelat, Anang, Zink, Erika E., Milasta, Sandra, Bajracharya, Resha, Oluwaseum, Ajayi J., Roussel, Martine F., Green, Douglas R., Pasa-Tolic, Ljiljana, & Thomas, Paul G.. Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention. Netherlands. https://doi.org/10.1016/j.celrep.2017.04.039
Smallwood, Heather S., Duan, Susu, Morfouace, Marie, Rezinciuc, Svetlana, Shulkin, Barry L., Shelat, Anang, Zink, Erika E., Milasta, Sandra, Bajracharya, Resha, Oluwaseum, Ajayi J., Roussel, Martine F., Green, Douglas R., Pasa-Tolic, Ljiljana, and Thomas, Paul G.. Mon . "Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention". Netherlands. https://doi.org/10.1016/j.celrep.2017.04.039.
@article{osti_1377984,
title = {Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention},
author = {Smallwood, Heather S. and Duan, Susu and Morfouace, Marie and Rezinciuc, Svetlana and Shulkin, Barry L. and Shelat, Anang and Zink, Erika E. and Milasta, Sandra and Bajracharya, Resha and Oluwaseum, Ajayi J. and Roussel, Martine F. and Green, Douglas R. and Pasa-Tolic, Ljiljana and Thomas, Paul G.},
abstractNote = {Influenza is a worldwide health and financial burden posing a significant risk to the immune-compromised, obese, diabetic, elderly, and pediatric populations. We identified increases in glucose metabolism in the lungs of pediatric patients infected with respiratory pathogens. Using quantitative mass spectrometry, we found metabolic changes occurring after influenza infection in primary human respiratory cells and validated infection-associated increases in c-Myc, glycolysis, and glutaminolysis. We confirmed these findings with a metabolic drug screen that identified the PI3K/mTOR inhibitor BEZ235 as a regulator of infectious virus production. BEZ235 treatment ablated the transient induction of c-Myc, restored PI3K/mTOR pathway homeostasis measured by 4E-BP1 and p85 phosphorylation, and reversed infection-induced changes in metabolism. Importantly, BEZ235 reduced infectious progeny but had no effect on the early stages of viral replication. BEZ235 significantly increased survival in mice, while reducing viral titer. We show metabolic reprogramming of host cells by influenza virus exposes targets for therapeutic intervention.},
doi = {10.1016/j.celrep.2017.04.039},
journal = {Cell Reports},
number = 8,
volume = 19,
place = {Netherlands},
year = {2017},
month = {5}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1016/j.celrep.2017.04.039

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Cited by: 6 works
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Works referencing / citing this record:

Influenza Virus Infections and Cellular Kinases
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  • Vrijens, Pieter; Noppen, Sam; Boogaerts, Talitha
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  • Eisenreich, Wolfgang; Rudel, Thomas; Heesemann, Jürgen
  • Frontiers in Cellular and Infection Microbiology, Vol. 9
  • DOI: 10.3389/fcimb.2019.00042

Immunometabolism and Pulmonary Infections: Implications for Protective Immune Responses and Host-Directed Therapies
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Inter-Species Host Gene Expression Differences in Response to Human and Avian Influenza A Virus Strains
journal, November 2017

  • Taye, Biruhalem; Yeo, Dawn; Lee, Raphael
  • International Journal of Molecular Sciences, Vol. 18, Issue 11
  • DOI: 10.3390/ijms18112295