The Attenuated Pseudorabies Virus Vaccine Strain Bartha Hyperactivates Plasmacytoid Dendritic Cells by Generating Large Amounts of Cell-Free Virus in Infected Epithelial Cells

Delva, Jonas L.; Waesberghe, Cliff Van; Broeck, Wim Van Den; Lamote, Jochen; Vereecke, Nick; Theuns, Sebastiaan; Couck, Liesbeth; Favoreel, Herman

doi:10.1128/jvi.02199-21

Cited by 5 publications

(4 citation statements)

References 90 publications

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“…Hence, although repair of the US region and the UL21 locus in the Bartha genome partially restored packaging of pUS3 and, to a lesser extent, IE180, the current data indicate that additional mechanisms are involved in the packaging defect of Bartha. Comparison of WT PRV and Bartha virions was done at 24 hpi. Previous research showed that PRV virions are assembled and/or released earlier in cells infected with PRV Bartha compared to cells infected with WT PRV (60). Hence, to assess whether or not the reduced incorporation of pUS3 and IE180 in Bartha virions may be time dependent, we analyzed Bartha virions harvested at 12 hpi.…”

Section: Resultsmentioning

confidence: 99%

“…We recently showed that the extracellular infectious virus titers of Bartha virions increase more rapidly early in infection of epithelial cells compared to those of Kaplan or Becker WT PRV (60). Despite this increased production of extracellular virus particles in Bartha-infected ST cells, intracellular production of structural viral proteins was similar in Bartha-versus WT PRV-infected cells, which led to the hypothesis of a more efficient assembly of Bartha virions (60). The current observation that fewer (tegument) proteins are incorporated in Bartha virions appears to be in line with this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

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Proteomic Comparison of Three Wild-Type Pseudorabies Virus Strains and the Attenuated Bartha Strain Reveals Reduced Incorporation of Several Tegument Proteins in Bartha Virions

Delva

Daled

Waesberghe

et al. 2022

J Virol

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Proteomic Comparison of Three Wild-Type Pseudorabies Virus Strains and the Attenuated Bartha Strain Reveals Reduced Incorporation of Several Tegument Proteins in Bartha Virions

Delva

Daled

Waesberghe

et al. 2022

J Virol

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“…The interaction between gI and gamma-secretase modulates the excessive phosphorylation of tau protein and beta-amyloid (Aβ), thereby elevating the risk of neurodegenerative disorders [39]. Concurrently, gI is also a virulence gene, which acts as a deletion gene in many herpes viruses to reduce the virulence of the virus to the host [40][41][42][43]. However, the function of N-glycosylation of gI as a glycoprotein in viral infection remains unknown.…”

Section: Discussionmentioning

confidence: 99%

N-glycosylation of envelope glycoprotein gI is crucial for the duck plague virus proliferation and virulence

Cheng,

Ning,

Wang

et al. 2024

Preprint

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Duck plague virus (DPV) causes highly pathogenic duck plague, and the envelope glycoprotein gI, as one of the key virulence genes, has not yet had its critical virulence sites identified through screening. In this study, reverse genetics technology was utilized to specifically target the gI protein within the genome of the DPV. Four mutant strains of DPV with mutations in the N-glycosylation sites of the gI protein were designed and constructed, and these mutant strains were successfully rescued. Our results confirmed that three asparagine residues (N69, N78, and N265) of gI are N-glycosylation sites, and Western blot analysis substantiated that the glycosylation at each predicted N-glycosylation site was compromised. The deglycosylation of gI results in the misfolding of the protein and its consequent retention in the endoplasmic reticulum (ER). For the subsequent intracellular transport of gI within duck embryonic fibroblasts (DEFs), the carrying effect of its interacting protein gE is essential. Compared to the parental virus, the mutated virus exhibits a reduced intercellular transmission capability to 66.3%. In ducks, the deglycosylation of gI significantly reduces the replication of DPV in vivo, thereby impairing the virulence of DPV. This research marks the first successful generation of an attenuated DPV strain through targeted mutations at the N-glycosylation sites. The findings provide a foundational understanding of DPV pathogenesis and offer a basis for the development of live attenuated vaccines against the disease.

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“…This may be due to the induction of a stronger immune response by the US2 deletion virus. Recent research has demonstrated that viruses with US2-deficient and gE/gI-deficient genes cause pDC to secrete more IFNα ( 44 ), suggesting that US2 might regulate antiviral immune responses. Consistently, in our results, US2-deficient PRV induced stronger immune responses in 3D4/21 cells, and the virus was less pathogenic in mice than wild-type PRV.…”

Section: Discussionmentioning

confidence: 99%

Pseudorabies virus tegument protein US2 antagonizes antiviral innate immunity by targeting cGAS-STING signaling pathway

Kong,

Chen,

Gong

et al. 2024

Front. Immunol.

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BackgroundThe cGAS-STING axis-mediated type I interferon pathway is a crucial strategy for host defense against DNA virus infection. Numerous evasion strategies developed by the pseudorabies virus (PRV) counteract host antiviral immunity. To what extent PRV-encoded proteins evade the cGAS-STING signaling pathway is unknown.MethodsUsing US2 stably expressing cell lines and US2-deficient PRV model, we revealed that the PRV tegument protein US2 reduces STING protein stability and downregulates STING-mediated antiviral signaling.ResultsTo promote K48-linked ubiquitination and STING degradation, US2 interacts with the LBD structural domain of STING and recruits the E3 ligase TRIM21. TRIM21 deficiency consistently strengthens the host antiviral immune response brought on by PRV infection. Additionally, US2-deficient PRV is less harmful in mice.ConclusionsOur study implies that PRV US2 inhibits IFN signaling by a new mechanism that selectively targets STING while successfully evading the host antiviral response. As a result, the present study reveals a novel strategy by which PRV evades host defense and offers explanations for why the Bartha-K61 classical vaccine strain failed to offer effective defense against PRV variant strains in China, indicating that US2 may be a key target for developing gene-deficient PRV vaccines.

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The Attenuated Pseudorabies Virus Vaccine Strain Bartha Hyperactivates Plasmacytoid Dendritic Cells by Generating Large Amounts of Cell-Free Virus in Infected Epithelial Cells

Abstract: The pseudorabies virus (PRV) vaccine strain Bartha has been and still is critical in the eradication of PRV in numerous countries. However, little is known about how this vaccine strain interacts with host cells and the host immune system.

Cited by 5 publications

References 90 publications

Proteomic Comparison of Three Wild-Type Pseudorabies Virus Strains and the Attenuated Bartha Strain Reveals Reduced Incorporation of Several Tegument Proteins in Bartha Virions

Proteomic Comparison of Three Wild-Type Pseudorabies Virus Strains and the Attenuated Bartha Strain Reveals Reduced Incorporation of Several Tegument Proteins in Bartha Virions

N-glycosylation of envelope glycoprotein gI is crucial for the duck plague virus proliferation and virulence

Pseudorabies virus tegument protein US2 antagonizes antiviral innate immunity by targeting cGAS-STING signaling pathway

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