Dataset Information

Pseudorabies Virus Infection of Epithelial Cells Leads to Persistent but Aberrant Activation of the NF-?B Pathway, Inhibiting Hallmark NF-?B-Induced Proinflammatory Gene Expression.

ABSTRACT: The nuclear factor kappa B (NF-?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-?B, illustrated by proteasome-dependent degradation of the inhibitory NF-?B regulator I?B and nuclear translocation and phosphorylation of the NF-?B subunit p65. PRV-induced persistent activation of NF-?B does not result in expression of negative feedback loop genes, like the gene for I?B? or A20, and does not trigger expression of prototypical proinflammatory genes, like the gene for tumor necrosis factor alpha (TNF-?) or interleukin-6 (IL-6). In addition, PRV infection inhibits TNF-?-induced canonical NF-?B activation. Hence, PRV infection triggers persistent NF-?B activation in an unorthodox way and dramatically modulates the NF-?B signaling axis, preventing typical proinflammatory gene expression and the responsiveness of cells to canonical NF-?B signaling, which may aid the virus in modulating early proinflammatory responses in the infected host.IMPORTANCE The NF-?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-?B, which does not result in expression of hallmark proinflammatory or negative feedback loop genes. In addition, although PRV-induced NF-?B activation shares some mechanistic features with canonical NF-?B activation, it also shows remarkable differences; e.g., it is largely independent of the canonical I?B kinase (IKK) and even renders infected cells resistant to canonical NF-?B activation by the inflammatory cytokine TNF-?. Aberrant PRV-induced NF-?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-?B activation.

SUBMITTER: Romero N

PROVIDER: S-EPMC7199412 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pseudorabies Virus Infection of Epithelial Cells Leads to Persistent but Aberrant Activation of the NF-κB Pathway, Inhibiting Hallmark NF-κB-Induced Proinflammatory Gene Expression.

Romero Nicolás N Van Waesberghe Cliff C Favoreel Herman W HW

Journal of virology 20200504 10

The nuclear factor kappa B (NF-κB) 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-κB, illustrated by proteasome-dependent ...[more]

PMID: 32132236

Similar Datasets

Project description:Intestinal barrier function defects and dysregulation of intestinal immune responses are two key contributory factors in the pathogenesis of ulcerative colitis (UC). Phenazine biosynthesis-like domain-containing protein (PBLD) was recently identified as a tumor suppressor in gastric cancer, hepatocellular carcinoma, and breast cancer; however, its role in UC remains unclear. Therefore, we analyzed colonic tissue samples from patients with UC and constructed specific intestinal epithelial PBLD-deficient (PBLDIEC-/-) mice to investigate the role of this protein in UC pathogenesis. We found that epithelial PBLD was decreased in patients with UC and was correlated with levels of tight junction (TJ) and inflammatory proteins. PBLDIEC-/- mice were more susceptible to dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid-induced colitis compared with wild-type (WT) mice. In DSS-induced colitis, PBLDIEC-/- mice had impaired intestinal barrier function and greater immune cell infiltration in colonic tissue than WT mice. Furthermore, TJ proteins were markedly reduced in PBLDIEC-/- mice compared with WT mice with colitis. Nuclear factor (NF)-κB activation was markedly elevated and resulted in higher expression levels of downstream effectors (C-C motif chemokine ligand 20, interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) in colonic epithelial cells isolated from PBLDIEC-/- mice than WT mice with colitis. PBLD overexpression in intestinal epithelial cells (IECs) consistently inhibited TNF-α/interferon-γ-induced intestinal barrier disruption and TNF-α-induced inflammatory responses via the suppression of NF-κB. In addition, IKK inhibition (IKK-16) rescued excessive inflammatory responses induced by TNF-α in PBLD knockdown FHC cells. Co-immunoprecipitation assays showed that PBLD may interact with IKKα and IKKβ, thus inhibiting NF-κB signaling, decreasing inflammatory mediator production, attenuating colonic inflammation, and improving intestinal barrier function. Modulating PBLD expression may provide a novel approach for treatment in patients with UC.

Project description:Simple Summary Pseudorabies virus (PRV) is a herpesvirus with zoonotic potential and has caused significant economic losses to the global pig industry. With the emergence of new mutants, the immune protection provided by vaccines has been greatly reduced, and it has become more difficulty to control PRV by vaccination. Recently, human cases of PRV-induced encephalitis have been reported, which suggest an urgent need for new control measures. In this study, we found that dihydromyricetin (DMY) exerted potent antiviral activity against PRV in vitro. DMY could ameliorate the PRV-induced abnormal activation of the NF-κB signaling pathway and excessive cellular inflammatory response. DMY could also induce the apoptosis of PRV-infected cells, thereby limiting the production of progeny virus. Based on the findings, DMY could be a candidate drug for the treatment of PRV infections. Abstract Pseudorabies virus (PRV) infections have caused huge economic losses to the breeding industry worldwide, especially pig husbandry. PRV could threaten human health as an easily ignored zoonotic pathogen. The emergence of new mutants significantly reduced the protective effect of vaccination, indicating an urgent need to develop specific therapeutic drugs for PRV infection. In this study, we found that dihydromyricetin (DMY) could dose-dependently restrain PRV infection in vitro with an IC50 of 161.34 μM; the inhibition rate of DMY at a concentration of 500 μM was 92.16 %. Moreover, the mode of action showed that DMY directly inactivated PRV virion and inhibited viral adsorption and cellular replication. DMY treatment could improve PRV-induced abnormal changes of the NF-κB signaling pathway and excessive inflammatory response through regulation of the contents of IκBα and p-P65/P65 and the transcriptional levels of cytokines (TNF-α, IL-1β and IL-6). Furthermore, DMY promoted the apoptosis of PRV-infected cells through the regulation of the expressions of Bax and Bcl-xl and the transcriptional levels of Caspase-3, Bax, Bcl-2 and Bcl-xl, thereby limiting the production of progeny virus. These findings indicated that DMY could be a candidate drug for the treatment of PRV infection.

Dataset Information

Pseudorabies Virus Infection of Epithelial Cells Leads to Persistent but Aberrant Activation of the NF-?B Pathway, Inhibiting Hallmark NF-?B-Induced Proinflammatory Gene Expression.

Publications

Pseudorabies Virus Infection of Epithelial Cells Leads to Persistent but Aberrant Activation of the NF-κB Pathway, Inhibiting Hallmark NF-κB-Induced Proinflammatory Gene Expression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets