The Construction and Immunogenicity Analyses of a Recombinant Pseudorabies Virus with Senecavirus A VP2 Protein Coexpression

Tao, Qian; Zhu, Ling; Xu, Lei; Yang, Yanting; Zhang, Yang; Liu, Zheyan; Xu, Tong; Wen, Jianhua; Deng, Lishuang; Zhou, Yuancheng; Xu, Zhiwen

doi:10.1128/spectrum.05229-22

Cited by 9 publications

(2 citation statements)

References 38 publications

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“…Research has shown that the PRV SA215 strain (TK - /gE - /gI - deleted) can be employed as a vector to insert PPV VP2 and EGFP expression box into the gI site using homologous recombination technology ( 18 ). Furthermore, gI and gE were replaced by the SVA VP2 and EGPF to obtain recombinant PRV ( 19 ). However, a major problem is that the foreign genes in recombinant PRV are only integrated into the genome for independent expression, rather than assembled on the surface of the virion.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, PRV infection is a public health concern. Given that PRV deleting non-essential genes, i.e., TK, gE, gI, and gG genes, attenuate its virulence ( 9 – 14 ), thus, the classical PRV has been described to express foreign antigen proteins to explore the feasibility of PRV as a potential vaccine vector, such as GP5 protein of porcine reproductive and respiratory syndrome virus (PRRSV) ( 15 ), E2 protein of classical swine fever virus (CSFV) ( 16 ), foot-and-mouth disease virus VP1 protein ( 17 ), porcine parvovirus (PPV) VP2 protein ( 18 ), and Senecavirus A (SVA) VP2 protein ( 19 ). However, the immunoprotective mechanism of a combined vaccine against the newly emerging pseudorabies virus type 2 and porcine circovirus type 2 has not been reported.…”

Section: Introductionmentioning

confidence: 99%

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Immunological characteristics of a recombinant alphaherpesvirus with an envelope-embedded Cap protein of circovirus

Lu,

Li,

Chen

et al. 2024

Front. Immunol.

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IntroductionVariant pseudorabies virus (PRV) is a newly emerged zoonotic pathogen that can cause human blindness. PRV can take advantage of its large genome and multiple non-essential genes to construct recombinant attenuated vaccines carrying foreign genes. However, a major problem is that the foreign genes in recombinant PRV are only integrated into the genome for independent expression, rather than assembled on the surface of virion.MethodsWe reported a recombinant PRV with deleted gE/TK genes and an inserted porcine circovirus virus 2 (PCV2) Cap gene into the extracellular domain of the PRV gE gene using the Cre-loxP recombinant system combined with the CRISPR-Cas9 gene editing system. This recombinant PRV (PRV-Cap), with the envelope-embedded Cap protein, exhibits a similar replication ability to its parental virus.ResultsAn immunogenicity assay revealed that PRV-Cap immunized mice have 100% resistance to lethal PRV and PCV2 attacks. Neutralization antibody and ELISPOT detections indicated that PRV-Cap can enhance neutralizing antibodies to PRV and produce IFN-γ secreting T cells specific for both PRV and PCV2. Immunological mechanistic investigation revealed that initial immunization with PRV-Cap stimulates significantly early activation and expansion of CD69+ T cells, promoting the activation of CD4 Tfh cell dependent germinal B cells and producing effectively specific effector memory T and B cells. Booster immunization with PRV-Cap recalled the activation of PRV-specific IFN-γ+IL-2+CD4+ T cells and IFN-γ+TNF-α+CD8+ T cells, as well as PCV2-specific IFN-γ+TNF-α+CD8+ T cells.ConclusionCollectively, our data suggested an immunological mechanism in that the recombinant PRV with envelope-assembled PCV2 Cap protein can serve as an excellent vaccine candidate for combined immunity against PRV and PCV2, and provided a cost-effective method for the production of PRV- PCV2 vaccine.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunological characteristics of a recombinant alphaherpesvirus with an envelope-embedded Cap protein of circovirus

Lu,

Li,

Chen

et al. 2024

Front. Immunol.

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The construction and immunogenicity analyses of a recombinant pseudorabies virus with Senecavirus A VP3 protein co-expression

Tao,

Xu,

Zhang

et al. 2024

Veterinary Microbiology

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The host cells suppress the proliferation of pseudorabies virus by regulating the PI3K/Akt/mTOR pathway

Xu,

Tao,

Zhang

et al. 2024

Microbiol Spectr

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Pseudorabies virus (PRV), a member of the alpha-herpesviruses, can infect both the nervous and reproductive systems of pigs, causing neonatal mortality and reproductive failure in sows, which incurs substantial economic losses. Neurotropism is a common characteristic of various viruses, allowing them to cross the blood-brain barrier and access the central nervous system. However, the precise mechanisms by which PRV affects the blood-brain barrier are not well understood. To investigate the mechanism of PRV’s interaction with the blood-brain barrier and its engagement with the PI3K/Akt signaling pathway during infection, an in vitro monolayer cell model of the blood-brain barrier was established. Our research found that PRV activates Matrix metallopeptidase 2 (MMP2), which degrades Zonula occludens-1 (ZO-1) and consequently enhances the permeability of the blood-brain barrier. PRV infection elevated the transcriptional levels of tissue inhibitor of metalloproteinases 1 (TIMP1) and inhibited its degradation through the ubiquitin-proteasome pathway, leading to higher intracellular concentrations of TIMP1 protein. TIMP1 regulates apoptosis and inhibits PRV replication in mouse brain microvascular endothelial cells through the PI3K/Akt/mTOR signaling pathway. In summary, our study delineates the mechanism through which PRV compromises the blood-brain barrier and provides insights into the host’s antiviral defense mechanisms post-infection. IMPORTANCE PRV, known for its neurotropic properties, is capable of inducing severe neuronal damage. Our study discovered that following PRV infection, the expression of MMP2 was upregulated, leading to the degradation of ZO-1. Furthermore, upon PRV infection in the host, the promoter of TIMP1 is significantly activated, resulting in a significant increase in TIMP1 protein levels. This upregulation of TIMP1 inhibits the proliferation of PRV through the PI3K/Akt signaling pathway. This study elucidated the mechanism through which PRV, including the PRV XJ delgE/gI/TK strains, compromises the blood-brain barrier and identifies the antiviral response characterized by the activation of the PI3K/Akt signaling pathway within infected host cells. These findings provide potential therapeutic targets for the clinical management and treatment of PRV.

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The Construction and Immunogenicity Analyses of a Recombinant Pseudorabies Virus with Senecavirus A VP2 Protein Coexpression

Cited by 9 publications

References 38 publications

Immunological characteristics of a recombinant alphaherpesvirus with an envelope-embedded Cap protein of circovirus

Immunological characteristics of a recombinant alphaherpesvirus with an envelope-embedded Cap protein of circovirus

The construction and immunogenicity analyses of a recombinant pseudorabies virus with Senecavirus A VP3 protein co-expression

The host cells suppress the proliferation of pseudorabies virus by regulating the PI3K/Akt/mTOR pathway

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