title: Antiviral effects of interferon-β are enhanced in the absence of the translational suppressor 4E-BP1 in myocarditis induced by Coxsackievirus B3.
abstract: BACKGROUND
  Viral myocarditis is most frequently associated with infection by Coxsackievirus B3 (CVB3). Interferon (IFN)-β therapy has been studied and could reduce virally induced tissue damage and improve heart function.
  
  
  METHODS
  In the present study we have investigated the role of translational suppression in the context of an IFN-α/β-mediated antiviral immune response to CVB3 infection. Specifically, we examined the effects of IFN-α/β treatment of CVB3-infected mouse embryonic fibroblast cells and splenocytes lacking eukaryotic initiation factor 4E binding protein-1 (4E-BP1), a suppressor of 5'-capped mRNA translation. Extending these in vitro studies, we examined the effects of CVB3 infection and IFN-β treatment in 4E-BP1(-/-) mice.
  
  
  RESULTS
  Our data show that 4E-BP1(-/-) cells are more -sensitive to the antiviral effects of IFN-α4 and IFN-β treatment than 4E-BP1(+/+) cells when infected with CVB3. Similarly, 4E-BP1(-/-) mice are more sensitive to treatment with IFN-β, exhibiting lower viral titres in heart tissue than 4E-BP1(+/+) mice during the course of infection. Additionally, we demonstrate that treatment with IFN-β reduces inflammatory infiltrates into the hearts of infected mice.
  
  
  CONCLUSIONS
  These data identify 4E-BP1 as a novel drug target to augment responsiveness to IFN-β therapy in CVB3-induced myocarditis.
authors.affiliation: Toronto General Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, ON, Canada.
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Burke
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000188:drug therapy* / Q000821:virology; D029822:Enterovirus B, Human / Q000187:drug effects; D039642:Eukaryotic Initiation Factors; D005347:Fibroblasts / Q000821:virology; D006367:HeLa Cells; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000188:drug therapy / Q000821:virology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D016899:Interferon-beta