Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication

Rhinoviruses (RVs) are responsible for the majority of upper airway infections; despite their high prevalence and the resulting economic burden, effective treatment is lacking. We report here that RV induces metabolic alterations in host cells, which offer an efficient target for antiviral intervent...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 30; pp. E7158 - E7165
Main Authors:	Gualdoni, Guido A., Mayer, Katharina A., Kapsch, Anna-Maria, Kreuzberg, Katharina, Puck, Alexander, Kienzl, Philip, Oberndorfer, Felicitas, Frühwirth, Karin, Winkler, Stefan, Blaas, Dieter, Zlabinger, Gerhard J., Stöckl, Johannes
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 24-07-2018
Series:	PNAS Plus
Subjects:	1-Phosphatidylinositol 3-kinase Animal models Animals Antiviral drugs Biological Sciences Cells Deoxyglucose Deoxyglucose - pharmacology Deprivation Female Glucose Glucose transporter Glucose Transporter Type 1 - genetics Glucose Transporter Type 1 - metabolism Glycolysis Infections Intervention Lipogenesis Lipogenesis - drug effects Lipogenesis - genetics Metabolism Metabolomics Mice Nucleotides - biosynthesis Nucleotides - genetics Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Picornaviridae Infections - drug therapy Picornaviridae Infections - genetics Picornaviridae Infections - metabolism Picornaviridae Infections - pathology PNAS Plus Replication Respiratory tract Rhinovirus Rhinovirus - physiology Target recognition Viral infections Virus Replication - drug effects Virus Replication - physiology Viruses metabolism metabolomics rhinovirus antiviral therapy
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Summary:	Rhinoviruses (RVs) are responsible for the majority of upper airway infections; despite their high prevalence and the resulting economic burden, effective treatment is lacking. We report here that RV induces metabolic alterations in host cells, which offer an efficient target for antiviral intervention. We show that RV-infected cells rapidly up-regulate glucose uptake in a PI3K-dependent manner. In parallel, infected cells enhance the expression of the PI3K-regulated glucose transporter GLUT1. In-depth metabolomic analysis of RV-infected cells revealed a critical role of glucose mobilization from extracellular and intracellular pools via glycogenolysis for viral replication. Infection resulted in a highly anabolic state, including enhanced nucleotide synthesis and lipogenesis. Consistently, we observed that glucose deprivation from medium and via glycolysis inhibition by 2-deoxyglucose (2-DG) potently impairs viral replication. Metabolomic analysis showed that 2-DG specifically reverts the RV-induced anabolic reprogramming. In addition, treatment with 2-DG inhibited RV infection and inflammation in a murine model. Thus, we demonstrate that the specific metabolic fingerprint of RV infection can be used to identify new targets for therapeutic intervention.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved June 21, 2018 (received for review January 10, 2018) Author contributions: G.A.G., G.J.Z., and J.S. designed research; G.A.G., K.A.M., A.-M.K., K.K., A.P., P.K., F.O., and K.F. performed research; P.K., S.W., D.B., G.J.Z., and J.S. contributed new reagents/analytic tools; G.A.G., K.A.M., K.K., A.P., F.O., D.B., and J.S. analyzed data; and G.A.G. and J.S. wrote the paper.
ISSN:	0027-8424 1091-6490 1091-6490
DOI:	10.1073/pnas.1800525115