title: Beta interferon regulation of glucose metabolism is PI3K/Akt dependent and important for antiviral activity against coxsackievirus B3.
abstract: An effective type I interferon (IFN)-mediated immune response requires the rapid expression of antiviral proteins that are necessary to inhibit viral replication and virus spread. We provide evidence that IFN-β regulates metabolic events important for the induction of a rapid antiviral response: IFN-β decreases the phosphorylation of AMP-activated protein kinase (AMPK), coincident with an increase in intracellular ATP. Our studies reveal a biphasic IFN-β-inducible uptake of glucose by cells, mediated by phosphatidylinositol 3-kinase (PI3K)/Akt, and IFN-β-inducible regulation of GLUT4 translocation to the cell surface. Additionally, we provide evidence that IFN-β-regulated glycolytic metabolism is important for the acute induction of an antiviral response during infection with coxsackievirus B3 (CVB3). Last, we demonstrate that the antidiabetic drug metformin enhances the antiviral potency of IFN-β against CVB3 both in vitro and in vivo. Taken together, these findings highlight an important role for IFN-β in modulating glucose metabolism during a virus infection and suggest that the use of metformin in combination with IFN-β during acute virus infection may result in enhanced antiviral responses.
  
  
  OBJECTIVE
  Type I interferons (IFN) are critical effectors of an antiviral response. These studies describe for the first time a role for IFN-β in regulating metabolism--glucose uptake and ATP production--to meet the energy requirements of a robust cellular antiviral response. Our data suggest that IFN-β regulates glucose metabolism mediated by signaling effectors similarly to activation by insulin. Interference with IFN-β-inducible glucose metabolism diminishes the antiviral response, whereas treatment with metformin, a drug that increases insulin sensitivity, enhances the antiviral potency of IFN-β.
authors.affiliation: Toronto General Research Institute, University Health Network, and Department of Immunology, University of Toronto, Toronto, Canada.
authors.forename: J D
authors.initials: JD
authors.lastname: Burke
authors.forename: L C
authors.initials: LC
authors.lastname: Platanias
authors.forename: E N
authors.initials: EN
authors.lastname: Fish
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D029822:Enterovirus B, Human / Q000235:genetics / Q000502:physiology*; D004769:Enterovirus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*
chemical_list: D016899:Interferon-beta; D000255:Adenosine Triphosphate; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D005947:Glucose