Constitutive activation of the transcription factor NF-kappaB results in impaired borna disease virus replication.
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.
Bourteele
Soizic
S
Institut für Immunologie, Friedrich Loeffler Institut, Bundesforschungsinstitut für Tiergesundheit, Paul Ehrlich Str. 28, 72076 Tübingen, Germany.
Oesterle
Katja
K
Pleschka
Stephan
S
Unterstab
Gunhild
G
Ehrhardt
Christina
C
Wolff
Thorsten
T
Ludwig
Stephan
S
Planz
Oliver
O
D000818:Animals; D001890:Borna Disease / Q000378:metabolism / Q000821:virology*; D001891:Borna disease virus / Q000235:genetics / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D005260:Female; D015967:Gene Expression Regulation, Viral; D006168:Guinea Pigs; D051550:I-kappa B Kinase; D007150:Immunohistochemistry; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014779:Virus Replication
D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase