Glycolysis Is an Intrinsic Factor for Optimal Replication of a Norovirus

ABSTRACT The metabolic pathways of central carbon metabolism, glycolysis and oxidative phosphorylation (OXPHOS), are important host factors that determine the outcome of viral infections and can be manipulated by some viruses to favor infection. However, mechanisms of metabolic modulation and their...

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Autores principales:	Karla D. Passalacqua, Jia Lu, Ian Goodfellow, Abimbola O. Kolawole, Jacob R. Arche, Robert J. Maddox, Kelly E. Carnahan, Mary X. D. O’Riordan, Christiane E. Wobus
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	calicivirus carbon metabolism glycolysis noroviruses oxidative phosphorylation pentose phosphate pathway Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/816f72c400f1417ea2ea221faebff586
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spelling	oai:doaj.org-article:816f72c400f1417ea2ea221faebff5862021-11-15T15:55:24ZGlycolysis Is an Intrinsic Factor for Optimal Replication of a Norovirus10.1128/mBio.02175-182150-7511https://doaj.org/article/816f72c400f1417ea2ea221faebff5862019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02175-18https://doaj.org/toc/2150-7511ABSTRACT The metabolic pathways of central carbon metabolism, glycolysis and oxidative phosphorylation (OXPHOS), are important host factors that determine the outcome of viral infections and can be manipulated by some viruses to favor infection. However, mechanisms of metabolic modulation and their effects on viral replication vary widely. Herein, we present the first metabolomics and energetic profiling of norovirus-infected cells, which revealed increases in glycolysis, OXPHOS, and the pentose phosphate pathway (PPP) during murine norovirus (MNV) infection. Inhibiting glycolysis with 2-deoxyglucose (2DG) in macrophages revealed that glycolysis is an important factor for optimal MNV infection, while inhibiting the PPP and OXPHOS showed a relatively minor impact of these pathways on MNV infection. 2DG affected an early stage in the viral life cycle after viral uptake and capsid uncoating, leading to decreased viral protein production and viral RNA. The requirement of glycolysis was specific for MNV (but not astrovirus) infection, independent of the type I interferon antiviral response, and unlikely to be due to a lack of host cell nucleotide synthesis. MNV infection increased activation of the protein kinase Akt, but not AMP-activated protein kinase (AMPK), two master regulators of cellular metabolism, implicating Akt signaling in upregulating host metabolism during norovirus infection. In conclusion, our findings suggest that the metabolic state of target cells is an intrinsic host factor that determines the extent of norovirus replication and implicates glycolysis as a virulence determinant. They further point to cellular metabolism as a novel therapeutic target for norovirus infections and improvements in current human norovirus culture systems. IMPORTANCE Viruses depend on the host cells they infect to provide the machinery and substrates for replication. Host cells are highly dynamic systems that can alter their intracellular environment and metabolic behavior, which may be helpful or inhibitory for an infecting virus. In this study, we show that macrophages, a target cell of murine norovirus (MNV), increase glycolysis upon viral infection, which is important for early steps in MNV infection. Human noroviruses (hNoV) are a major cause of gastroenteritis globally, causing enormous morbidity and economic burden. Currently, no effective antivirals or vaccines exist for hNoV, mainly due to the lack of high-efficiency in vitro culture models for their study. Thus, insights gained from the MNV model may reveal aspects of host cell metabolism that can be targeted for improving hNoV cell culture systems and for developing effective antiviral therapies.Karla D. PassalacquaJia LuIan GoodfellowAbimbola O. KolawoleJacob R. ArcheRobert J. MaddoxKelly E. CarnahanMary X. D. O’RiordanChristiane E. WobusAmerican Society for Microbiologyarticlecaliciviruscarbon metabolismglycolysisnorovirusesoxidative phosphorylationpentose phosphate pathwayMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	calicivirus carbon metabolism glycolysis noroviruses oxidative phosphorylation pentose phosphate pathway Microbiology QR1-502
spellingShingle	calicivirus carbon metabolism glycolysis noroviruses oxidative phosphorylation pentose phosphate pathway Microbiology QR1-502 Karla D. Passalacqua Jia Lu Ian Goodfellow Abimbola O. Kolawole Jacob R. Arche Robert J. Maddox Kelly E. Carnahan Mary X. D. O’Riordan Christiane E. Wobus Glycolysis Is an Intrinsic Factor for Optimal Replication of a Norovirus
description	ABSTRACT The metabolic pathways of central carbon metabolism, glycolysis and oxidative phosphorylation (OXPHOS), are important host factors that determine the outcome of viral infections and can be manipulated by some viruses to favor infection. However, mechanisms of metabolic modulation and their effects on viral replication vary widely. Herein, we present the first metabolomics and energetic profiling of norovirus-infected cells, which revealed increases in glycolysis, OXPHOS, and the pentose phosphate pathway (PPP) during murine norovirus (MNV) infection. Inhibiting glycolysis with 2-deoxyglucose (2DG) in macrophages revealed that glycolysis is an important factor for optimal MNV infection, while inhibiting the PPP and OXPHOS showed a relatively minor impact of these pathways on MNV infection. 2DG affected an early stage in the viral life cycle after viral uptake and capsid uncoating, leading to decreased viral protein production and viral RNA. The requirement of glycolysis was specific for MNV (but not astrovirus) infection, independent of the type I interferon antiviral response, and unlikely to be due to a lack of host cell nucleotide synthesis. MNV infection increased activation of the protein kinase Akt, but not AMP-activated protein kinase (AMPK), two master regulators of cellular metabolism, implicating Akt signaling in upregulating host metabolism during norovirus infection. In conclusion, our findings suggest that the metabolic state of target cells is an intrinsic host factor that determines the extent of norovirus replication and implicates glycolysis as a virulence determinant. They further point to cellular metabolism as a novel therapeutic target for norovirus infections and improvements in current human norovirus culture systems. IMPORTANCE Viruses depend on the host cells they infect to provide the machinery and substrates for replication. Host cells are highly dynamic systems that can alter their intracellular environment and metabolic behavior, which may be helpful or inhibitory for an infecting virus. In this study, we show that macrophages, a target cell of murine norovirus (MNV), increase glycolysis upon viral infection, which is important for early steps in MNV infection. Human noroviruses (hNoV) are a major cause of gastroenteritis globally, causing enormous morbidity and economic burden. Currently, no effective antivirals or vaccines exist for hNoV, mainly due to the lack of high-efficiency in vitro culture models for their study. Thus, insights gained from the MNV model may reveal aspects of host cell metabolism that can be targeted for improving hNoV cell culture systems and for developing effective antiviral therapies.
format	article
author	Karla D. Passalacqua Jia Lu Ian Goodfellow Abimbola O. Kolawole Jacob R. Arche Robert J. Maddox Kelly E. Carnahan Mary X. D. O’Riordan Christiane E. Wobus
author_facet	Karla D. Passalacqua Jia Lu Ian Goodfellow Abimbola O. Kolawole Jacob R. Arche Robert J. Maddox Kelly E. Carnahan Mary X. D. O’Riordan Christiane E. Wobus
author_sort	Karla D. Passalacqua
title	Glycolysis Is an Intrinsic Factor for Optimal Replication of a Norovirus
title_short	Glycolysis Is an Intrinsic Factor for Optimal Replication of a Norovirus
title_full	Glycolysis Is an Intrinsic Factor for Optimal Replication of a Norovirus
title_fullStr	Glycolysis Is an Intrinsic Factor for Optimal Replication of a Norovirus
title_full_unstemmed	Glycolysis Is an Intrinsic Factor for Optimal Replication of a Norovirus
title_sort	glycolysis is an intrinsic factor for optimal replication of a norovirus
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/816f72c400f1417ea2ea221faebff586
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Glycolysis Is an Intrinsic Factor for Optimal Replication of a Norovirus

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