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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 Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
Sponsoring Org.:
USDOE
OSTI Identifier:
1371999
Report Number(s):
PNNL-SA-127228
Journal ID: ISSN 2211-1247; 34745; KP1704020
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Cell Reports; Journal Volume: 19; Journal Issue: 8
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Environmental Molecular Sciences Laboratory

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. United States: N. p., 2017. Web. doi: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. United States. doi: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". United States. doi:10.1016/j.celrep.2017.04.039.
@article{osti_1371999,
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 = {United States},
year = {Mon May 01 00:00:00 EDT 2017},
month = {Mon May 01 00:00:00 EDT 2017}
}