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Title: Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention

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:
 [1] ;  [2] ;  [2] ;  [1] ;  [2] ;  [2] ;  [3] ;  [2] ;  [2] ;  [1] ;  [2] ;  [2] ;  [3] ;  [2]
  1. Univ. of Tennessee Health Science Center, Memphis, TN (United States)
  2. St. Jude Children's Research Hospital, Memphis, TN (United States)
  3. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Publication Date:
Grant/Contract Number:
AC0576RL01830; AC05-76RL0 1830
Type:
Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 19; Journal Issue: 8; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Research Org:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES
OSTI Identifier:
1377984
Alternate Identifier(s):
OSTI ID: 1364393

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., 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.. 2017. "Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention". United States. doi: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 = {United States},
year = {2017},
month = {5}
}