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The influenza A virus genotype determines the anti-viral function of NF-κB

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  • The influenza A virus genotype determines the anti-viral function of NF-κB

    J Virol. 2016 Jun 29. pii: JVI.00946-16. [Epub ahead of print]
    The influenza A virus genotype determines the anti-viral function of NF-κB.

    Dam S1, Kracht M2, Pleschka S3, Schmitz ML4.
    Author information

    Abstract

    The role of NF-κB for influenza A virus (IAV) infection does not reveal a coherent picture, as pro- and also anti-viral functions of this transcription factor have been described. To address this issue, we used CRISPR-Cas9-mediated genome engineering to generate murine MLE-15 cells lacking two essential components of the NF-κB pathway. Cells devoid of either the central NF-κB essential modulator (NEMO) scaffold protein and thus defect in IκB kinase (IKK) activation or cells not expressing the NF-κB DNA-binding and transactivation subunit p65 were tested for propagation of the SC35 virus, which has an avian host range and its mouse-adapted variant SC35M. While NF-κB was not relevant for replication of SC35M, the absence of NF-κB activity increased replication of the non-adapted SC35. This anti-viral effect of NF-κB was most prominent upon infection of cells with low virus titers as they usually occur during the initiation phase of IAV infection. Defect NF-κB signaling resulted in diminished IAV-triggered phosphorylation of IRF3 and expression of the anti-viral IFNβ gene. To identify the viral proteins responsible for NF-κB-dependency, reassortant viruses were generated by reverse genetics. SC35 viruses containing the SC35M segment encoding neuraminidase (NA) were completely inert to the inhibitory effect of NF-κB, emphasizing the importance of the viral genotype for susceptibility to the anti-viral functions of NF-κB.
    IMPORTANCE:

    This study addresses two different issues: First, we investigated the role of the host cell transcription factor NF-κB for IAV replication by genetic manipulation of IAVs by reverse genetics combined with targeted genome engineering of host cells using CRISPR-Cas9. The analysis of these two highly defined genetic systems indicated that the IAV genotype can influence whether NF-κB displays an anti-viral function, and thus might in part explain incoherent results from the literature. Second, we found that perturbation of NF-κB function greatly improved the growth of a non-adapted IAV, suggesting that NF-κB may contribute to the maintenance of the host species barrier.
    Copyright ? 2016, American Society for Microbiology. All Rights Reserved.


    PMID: 27356900 DOI: 10.1128/JVI.00946-16
    [PubMed - as supplied by publisher]
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