Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention

被引:120
|
作者
Smallwood, Heather S. [1 ]
Duan, Susu [2 ]
Morfouace, Marie [3 ]
Rezinciuc, Svetlana [1 ]
Shulkin, Barry L. [3 ,5 ]
Shelat, Anang [6 ]
Zink, Erika E. [1 ]
Milasta, Sandra [2 ]
Bajracharya, Resha [2 ]
Oluwaseum, Ajayi J. [1 ]
Roussel, Martine F. [3 ]
Green, Douglas R. [2 ]
Pasa-Tolic, Ljiljana [4 ]
Thomas, Paul G. [2 ]
机构
[1] Univ Tennessee, Hlth Sci Ctr, Dept Pediat, Memphis, TN 38103 USA
[2] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA
[3] St Jude Childrens Res Hosp, Dept Tumor Cell Biol, Memphis, TN 38105 USA
[4] Pacific Northwest Natl Lab, Dept Biol Sci Div, Richland, WA 99352 USA
[5] St Jude Childrens Res Hosp, Dept Radiol Sci, Memphis, TN 38105 USA
[6] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA
来源
CELL REPORTS | 2017年 / 19卷 / 08期
关键词
C-MYC; HUMAN CYTOMEGALOVIRUS; A VIRUS; GLUTAMINE UTILIZATION; CELLS; GLYCOLYSIS; REPLICATION; INHIBITORS; PATHWAY; GLUCOSE;
D O I
10.1016/j.celrep.2017.04.039
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:1640 / 1653
页数:14
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