Constitutive Activation of the Transcription Factor NF-?B Results in Impaired Borna Disease Virus Replication #MMPMID15857990
Bourteele S; Oesterle K; Pleschka S; Unterstab G; Ehrhardt C; Wolff T; Ludwig S; Planz O
J Virol 2005[May]; 79 (10): 6043-51 PMID15857990garesp_yesshow ga
The inducible transcription factor NF-?B 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-?B 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-?B signaling pathway. While BDV titers were not affected in cells with impaired NF-?B signaling, the expression of an activated mutant of I?B 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-?B 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-?B 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-?B preferentially spread to areas of the brains of infected rats where activated NF-?B was not detectable.
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