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Pseudorabies virus infection of epithelial cells leads to persistent but aberrant activation of the NF-kappa B pathway, inhibiting hallmark NF-kappa B-induced proinflammatory gene expression

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Abstract
The nuclear factor kappa B (NF-kappa B) is a potent transcription factor, activation of which typically results in robust proinflammatory signaling and triggering of fast negative feedback modulators to avoid excessive inflammatory responses. Here, we report that infection of epithelial cells, including primary porcine respiratory epithelial cells, with the porcine alphaherpesvirus pseudorabies virus (PRV) results in the gradual and persistent activation of NF-kappa B, illustrated by proteasome-dependent degradation of the inhibitory NF-kappa B regulator I kappa B and nuclear translocation and phosphorylation of the NF-kappa B subunit p65. PRVinduced persistent activation of NF-kappa B does not result in expression of negative feedback loop genes, like the gene for I kappa B alpha or A20, and does not trigger expression of prototypical proinflammatory genes, like the gene for tumor necrosis factor alpha (TNF-alpha) or interleukin-6 (IL-6). In addition, PRV infection inhibits TNF-alpha induced canonical NF-kappa B activation. Hence, PRV infection triggers persistent NF-kappa B activation in an unorthodox way and dramatically modulates the NF-kappa B signaling axis, preventing typical proinflammatory gene expression and the responsiveness of cells to canonical NF-kappa B signaling, which may aid the virus in modulating early proinflammatory responses in the infected host. IMPORTANCE The NF-kappa B transcription factor is activated via different key inflammatory pathways and typically results in the fast expression of several proinflammatory genes as well as negative feedback loop genes to prevent excessive inflammation. In the current report, we describe that infection of cells with the porcine alphaherpesvirus pseudorabies virus (PRV) triggers a gradual and persistent aberrant activation of NF-kappa B, which does not result in expression of hallmark proinflammatory or negative feedback loop genes. In addition, although PRV-induced NF-kappa B activation shares some mechanistic features with canonical NF-kappa B activation, it also shows remarkable differences; e.g., it is largely independent of the canonical I kappa B kinase (IKK) and even renders infected cells resistant to canonical NF-kappa B activation by the inflammatory cytokine TNF-alpha. Aberrant PRV-induced NF-kappa B activation may therefore paradoxically serve as a viral immune evasion strategy and may represent an important tool to unravel currently unknown mechanisms and consequences of NF-kappa B activation.
Keywords
TUMOR-NECROSIS-FACTOR, US3 PROTEIN-KINASE, HERPES-SIMPLEX, FACTOR-ALPHA, TRANSCRIPTIONAL ACTIVATION, NUCLEAR TRANSLOCATION, PHOSPHORYLATION, INDUCTION, TYPE-1, SIGNAL, NF-kappa B, evasion, herpes, innate, pseudorabies virus

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MLA
Romero Rata, Nicolás, et al. “Pseudorabies Virus Infection of Epithelial Cells Leads to Persistent but Aberrant Activation of the NF-Kappa B Pathway, Inhibiting Hallmark NF-Kappa B-Induced Proinflammatory Gene Expression.” JOURNAL OF VIROLOGY, vol. 94, no. 10, 2020, doi:10.1128/JVI.00196-20.
APA
Romero Rata, N., Van Waesberghe, C., & Favoreel, H. (2020). Pseudorabies virus infection of epithelial cells leads to persistent but aberrant activation of the NF-kappa B pathway, inhibiting hallmark NF-kappa B-induced proinflammatory gene expression. JOURNAL OF VIROLOGY, 94(10). https://doi.org/10.1128/JVI.00196-20
Chicago author-date
Romero Rata, Nicolás, Cliff Van Waesberghe, and Herman Favoreel. 2020. “Pseudorabies Virus Infection of Epithelial Cells Leads to Persistent but Aberrant Activation of the NF-Kappa B Pathway, Inhibiting Hallmark NF-Kappa B-Induced Proinflammatory Gene Expression.” JOURNAL OF VIROLOGY 94 (10). https://doi.org/10.1128/JVI.00196-20.
Chicago author-date (all authors)
Romero Rata, Nicolás, Cliff Van Waesberghe, and Herman Favoreel. 2020. “Pseudorabies Virus Infection of Epithelial Cells Leads to Persistent but Aberrant Activation of the NF-Kappa B Pathway, Inhibiting Hallmark NF-Kappa B-Induced Proinflammatory Gene Expression.” JOURNAL OF VIROLOGY 94 (10). doi:10.1128/JVI.00196-20.
Vancouver
1.
Romero Rata N, Van Waesberghe C, Favoreel H. Pseudorabies virus infection of epithelial cells leads to persistent but aberrant activation of the NF-kappa B pathway, inhibiting hallmark NF-kappa B-induced proinflammatory gene expression. JOURNAL OF VIROLOGY. 2020;94(10).
IEEE
[1]
N. Romero Rata, C. Van Waesberghe, and H. Favoreel, “Pseudorabies virus infection of epithelial cells leads to persistent but aberrant activation of the NF-kappa B pathway, inhibiting hallmark NF-kappa B-induced proinflammatory gene expression,” JOURNAL OF VIROLOGY, vol. 94, no. 10, 2020.
@article{8668100,
  abstract     = {The nuclear factor kappa B (NF-kappa B) is a potent transcription factor, activation of which typically results in robust proinflammatory signaling and triggering of fast negative feedback modulators to avoid excessive inflammatory responses. Here, we report that infection of epithelial cells, including primary porcine respiratory epithelial cells, with the porcine alphaherpesvirus pseudorabies virus (PRV) results in the gradual and persistent activation of NF-kappa B, illustrated by proteasome-dependent degradation of the inhibitory NF-kappa B regulator I kappa B and nuclear translocation and phosphorylation of the NF-kappa B subunit p65. PRVinduced persistent activation of NF-kappa B does not result in expression of negative feedback loop genes, like the gene for I kappa B alpha or A20, and does not trigger expression of prototypical proinflammatory genes, like the gene for tumor necrosis factor alpha (TNF-alpha) or interleukin-6 (IL-6). In addition, PRV infection inhibits TNF-alpha induced canonical NF-kappa B activation. Hence, PRV infection triggers persistent NF-kappa B activation in an unorthodox way and dramatically modulates the NF-kappa B signaling axis, preventing typical proinflammatory gene expression and the responsiveness of cells to canonical NF-kappa B signaling, which may aid the virus in modulating early proinflammatory responses in the infected host. IMPORTANCE The NF-kappa B transcription factor is activated via different key inflammatory pathways and typically results in the fast expression of several proinflammatory genes as well as negative feedback loop genes to prevent excessive inflammation. In the current report, we describe that infection of cells with the porcine alphaherpesvirus pseudorabies virus (PRV) triggers a gradual and persistent aberrant activation of NF-kappa B, which does not result in expression of hallmark proinflammatory or negative feedback loop genes. In addition, although PRV-induced NF-kappa B activation shares some mechanistic features with canonical NF-kappa B activation, it also shows remarkable differences; e.g., it is largely independent of the canonical I kappa B kinase (IKK) and even renders infected cells resistant to canonical NF-kappa B activation by the inflammatory cytokine TNF-alpha. Aberrant PRV-induced NF-kappa B activation may therefore paradoxically serve as a viral immune evasion strategy and may represent an important tool to unravel currently unknown mechanisms and consequences of NF-kappa B activation.},
  articleno    = {e00196-20},
  author       = {Romero Rata, Nicolás and Van Waesberghe, Cliff and Favoreel, Herman},
  issn         = {0022-538X},
  journal      = {JOURNAL OF VIROLOGY},
  keywords     = {TUMOR-NECROSIS-FACTOR,US3 PROTEIN-KINASE,HERPES-SIMPLEX,FACTOR-ALPHA,TRANSCRIPTIONAL ACTIVATION,NUCLEAR TRANSLOCATION,PHOSPHORYLATION,INDUCTION,TYPE-1,SIGNAL,NF-kappa B,evasion,herpes,innate,pseudorabies virus},
  language     = {eng},
  number       = {10},
  pages        = {24},
  title        = {Pseudorabies virus infection of epithelial cells leads to persistent but aberrant activation of the NF-kappa B pathway, inhibiting hallmark NF-kappa B-induced proinflammatory gene expression},
  url          = {http://dx.doi.org/10.1128/JVI.00196-20},
  volume       = {94},
  year         = {2020},
}

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