Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention

Heather Smallwood, Susu Duan, Marie Morfouace, Svetlana Rezinciuc, Barry L. Shulkin, Anang Shelat, Erika E. Zink, Sandra Milasta, Resha Bajracharya, Ajayi J. Oluwaseum, Martine F. Roussel, Douglas R. Green, Ljiljana Pasa-Tolic, Paul G. Thomas

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1640-1653
Number of pages14
JournalCell Reports
Volume19
Issue number8
DOIs
StatePublished - May 23 2017

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Human Influenza
Pediatrics
Infection
Phosphatidylinositol 3-Kinases
Viruses
Metabolism
Phosphorylation
Pathogens
Glycolysis
Therapeutics
Orthomyxoviridae
Mass spectrometry
Mass Spectrometry
Homeostasis
Health
Glucose
Lung
Survival
dactolisib
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention. / Smallwood, Heather; 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.

In: Cell Reports, Vol. 19, No. 8, 23.05.2017, p. 1640-1653.

Research output: Contribution to journalArticle

Smallwood, H, Duan, S, Morfouace, M, Rezinciuc, S, Shulkin, BL, Shelat, A, Zink, EE, Milasta, S, Bajracharya, R, Oluwaseum, AJ, Roussel, MF, Green, DR, Pasa-Tolic, L & Thomas, PG 2017, 'Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention', Cell Reports, vol. 19, no. 8, pp. 1640-1653. https://doi.org/10.1016/j.celrep.2017.04.039
Smallwood, Heather ; 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. In: Cell Reports. 2017 ; Vol. 19, No. 8. pp. 1640-1653.
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