Constitutive activation of the transcription factor NF-kappaB results in impaired borna disease virus replication

J Virol. 2005 May;79(10):6043-51. doi: 10.1128/JVI.79.10.6043-6051.2005.

Abstract

The inducible transcription factor NF-kappaB is commonly activated upon RNA virus infection and is a key player in the induction and regulation of the innate immune response. Borna disease virus (BDV) is a neurotropic negative-strand RNA virus, which replicates in the nucleus of the infected cell and causes a persistent infection that can lead to severe neurological disorders. To investigate the activation and function of NF-kappaB in BDV-infected cells, we stably transfected the highly susceptible neuronal guinea pig cell line CRL with a constitutively active (IKK EE) or dominant-negative (IKK KD) regulator of the IKK/NF-kappaB signaling pathway. While BDV titers were not affected in cells with impaired NF-kappaB signaling, the expression of an activated mutant of IkappaB kinase (IKK) resulted in a strong reduction in the intracellular viral titer in CRL cells. Electrophoretic mobility shift assays and luciferase reporter gene assays revealed that neither NF-kappaB nor interferon regulatory factors (IRFs) were activated upon acute BDV infection of wild-type or vector-transfected CRL cells. However, when IKK EE-transfected cells were used as target cells for BDV infection, DNA binding to an IRF3/7-responsive DNA element was detectable. Since IRF3/7 is a key player in the antiviral interferon response, our data indicate that enhanced NF-kappaB activity in the presence of BDV leads to the induction of antiviral pathways resulting in reduced virus titers. Consistent with this observation, the anti-BDV activity of NF-kappaB preferentially spread to areas of the brains of infected rats where activated NF-kappaB was not detectable.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Borna Disease / metabolism
  • Borna Disease / virology*
  • Borna disease virus / genetics
  • Borna disease virus / physiology*
  • Brain / metabolism
  • Cell Line
  • Female
  • Gene Expression Regulation, Viral*
  • Guinea Pigs
  • I-kappa B Kinase
  • Immunohistochemistry
  • NF-kappa B / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Signal Transduction
  • Virus Replication

Substances

  • NF-kappa B
  • Protein Serine-Threonine Kinases
  • I-kappa B Kinase