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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}
}
  • 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-BP1more » 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.« less
  • 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-BP1more » 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.« less
  • Amantadine HCl administration has resulted in accelerated resolution of influenza A illness. Prolonged abnormalities in pulmonary function have been described in uncomplicated influenza A. To study the effect of amantadine on these changes, we evaluated young adults with documented natural influenza A with clear chest examinations and x rays. Subjects received placebo or amantadine in random, double-blind fashion. Physiologic studies included maximal expiratory flow volume curves with air and helium-oxygen mixtures. Air flow rates were unchanged in all subjects throughout. Initially, both groups showed comparable decreases in mean helium-oxygen maximal expiratory flow rates. The amantadine group showed accelerated physiologic improvement:more » significant increase in helium-oxygen, flow rates occurred within 7 days (P < 0.05). The rate of improvement in the helium-oxygen flow rates in the placebo group was not statistically significant. These studies confirm peripheral airways dysfunction after uncomplicated influenza A and suggest that amantadine is associated with accelerated resolution of this dysfunction.« less
  • Influenza A are nuclear replicating viruses which hijack host machineries in order to achieve optimal infection. Numerous functional virus-host interactions have now been characterized, but little information has been gathered concerning their link to the virally induced remodeling of the host cellular architecture. In this study, we infected cells with several human and avian influenza viruses and we have analyzed their ultrastructural modifications by using electron and confocal microscopy. We discovered that infections lead to a major and systematic disruption of nucleoli and the formation of a large number of diverse viral structures showing specificity that depended on the subtypemore » origin and genomic composition of viruses. We identified NS1 and M1 proteins as the main actors in the remodeling of the host ultra-structure and our results suggest that each influenza A virus strain could be associated with a specific cellular fingerprint, possibly correlated to the functional properties of their viral components.« less
  • The ability of Leishmania to survive in their insect or mammalian host is dependent upon an ability to sense and adapt to changes in the microenvironment. However, little is known about the molecular mechanisms underlying the parasite response to environmental changes, such as nutrient availability. To elucidate nutrient stress response pathways in Leishmania donovani, we have used purine starvation as the paradigm. The salvage of purines from the host milieu is obligatory for parasite replication; nevertheless, purine-starved parasites can persist in culture without supplementary purine for over 3 months, indicating that the response to purine starvation is robust and engendersmore » parasite survival under conditions of extreme scarcity. To understand metabolic reprogramming during purine starvation we have employed global approaches. Whole proteome comparisons between purine-starved and purine-replete parasites over a 6-48 h span have revealed a temporal and coordinated response to purine starvation. Purine transporters and enzymes involved in acquisition at the cell surface are upregulated within a few hours of purine removal from the media, while other key purine salvage components are upregulated later in the time-course and more modestly. After 48 h, the proteome of purine-starved parasites is extensively remodeled and adaptations to purine stress appear tailored to deal with both purine deprivation and general stress. To probe the molecular mechanisms affecting proteome remodeling in response to purine starvation, comparative RNA-seq analyses, qRT-PCR, and luciferase reporter assays were performed on purine-starved versus purine-replete parasites. While the regulation of a minority of proteins tracked with changes at the mRNA level, for many regulated proteins it appears that proteome remodeling during purine stress occurs primarily via translational and/or post-translational mechanisms.« less