Pseudorabies Virus US3 Protein Inhibits IFN-β Production by Interacting With IRF3 to Block Its Activation

Xie, Jingyuan; Zhang, Xiangbo; Chen, Lei; Bi, Yingjie; Idris, Adi; Xu, Shujuan; Li, Xiangrong; Zhang, Yong; Feng, Ru

doi:10.3389/fmicb.2021.761282

Cited by 17 publications

(11 citation statements)

References 53 publications

(52 reference statements)

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“…Many viruses, including herpesviruses have evolved various strategies to suppress apoptosis of infected cells and evade cell-mediated immune response by encoding multiple anti-apoptotic genes. The US3 protein kinase encoded by herpes simplex virus type-1 (HSV-1) or PRV could block apoptosis induced by overexpression pro-apoptotic family members of Bad or Bcl-2 [ 32 , 33 , 34 ]. We also demonstrated that the function of PRV ΔgE/TK/US3 inhibiting infected cell apoptosis is decreased after deletion of US3 gene.…”

Section: Discussionmentioning

confidence: 99%

The Deletion of US3 Gene of Pseudorabies Virus (PRV) ΔgE/TK Strain Induces Increased Immunogenicity in Mice

et al. 2022

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Re-emerging pseudorabies (PR) caused by pseudorabies virus (PRV) variant has been prevailing among immunized herds in China since 2011, indicating that commercially available PR vaccine strains couldn’t provide complete protection against novel, epidemic PRV variant. Before this study, a gE/TK-gene-deleted virus (PRV ΔgE/TK) was constructed from PRV QYY2012 variant through homologous recombination and Cre/LoxP system. Here, PRV ΔgE/TK/US3 strain was generated by deleting US3 gene based on PRV ΔgE/TK strain using the same method. The growth characteristics of PRV ΔgE/TK/US3 were analogous to that of PRV ΔgE/TK. Moreover, the deletion of US3 gene could promote apoptosis, upregulate the level of swine leukocyte antigen class I molecule (SLA-I) in vitro, and relieve inflammatory response in inoculated BALB/c mice. Subsequently, the safety and immunogenicity of PRV ΔgE/TK/US3 was evaluated as a vaccine candidate in mice. The results revealed that PRV ΔgE/TK/US3 was safe for mice, and mice vaccinated with PRV ΔgE/TK/US3 could induce a higher level of PRV-specific neutralizing antibodies and cytokines, including IFN-γ, IL-2 and IL-4, also higher level of CD8+ CD69+ Tissue-Resident Memory T cells (TRM). The results show that the deletion of US3 gene of PRV ΔgE/TK strain could induce increased immunogenicity, indicating that the PRV ΔgE/TK/US3 strain is a promising vaccine candidate for preventing and controlling of the epidemic PR in China.

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Section: Discussionmentioning

confidence: 99%

The Deletion of US3 Gene of Pseudorabies Virus (PRV) ΔgE/TK Strain Induces Increased Immunogenicity in Mice

et al. 2022

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“…This rapid shutdown of interferon production is carried out by viral tegument proteins that are released during entry of the virus and by (immediate) early viral proteins. For example, the UL13 tegument protein kinase of PRV suppresses type I IFN production via degradation of PRDX1, IRF3 and STING ( 30 – 32 ), the US3 tegument protein kinase of PRV triggers degradation of IRF3 and Bclaf1 to suppress type I IFN production ( 33 , 34 ), and the early EP0 protein of PRV antagonizes type I IFN production by inhibiting IRF9 ( 35 ). Hence, although speculative, we hypothesize that, in comparison with low MOI infection, high MOI PRV infection leads to increased intracellular concentration of incoming tegument viral proteins and increased production of (immediate) early viral proteins, which counteract the type I IFN response.…”

Section: Discussionmentioning

confidence: 99%

Pseudorabies virus-induced expression and antiviral activity of type I or type III interferon depend on the type of infected epithelial cell

Yuan

Ma²,

Waesberghe³

et al. 2022

Front. Immunol.

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Type I and III Interferons (IFNs) are the initial antiviral cytokines produced in response to virus infection. These IFNs in turn bind to their respective receptors, trigger JAK-STAT signaling and induce the expression of IFN-stimulated genes (ISGs) to engage antiviral functions. Unlike the receptor for type I IFNs, which is broadly expressed, the expression of the type III IFN receptor is mainly confined to epithelial cells that line mucosal surfaces. Accumulating evidence has shown that type III IFNs may play a unique role in protecting mucosal surfaces against viral challenges. The porcine alphaherpesvirus pseudorabies virus (PRV) causes huge economic losses to the pig industry worldwide. PRV first replicates in the respiratory tract, followed by spread via neurons and via lymph and blood vessels to the central nervous system and internal organs, e.g. the kidney, lungs and intestinal tract. In this study, we investigate whether PRV triggers the expression of type I and III IFNs and whether these IFNs exert antiviral activity against PRV in different porcine epithelial cells: porcine kidney epithelial cells (PK-15), primary respiratory epithelial cells (PoREC) and intestinal porcine epithelial cells (IPEC-J2). We show that PRV triggers a multiplicity of infection-dependent type I IFN response and a prominent III IFN response in PK-15 cells, a multiplicity of infection-dependent expression of both types of IFN in IPEC-J2 cells and virtually no expression of either IFN in PoREC. Pretreatment of the different cell types with equal amounts of porcine IFN-λ3 (type III IFN) or porcine IFN-α (type I IFN) showed that IFN-α, but not IFN-λ3, suppressed PRV replication and spread in PK-15 cells, whereas the opposite was observed in IPEC-J2 cells and both types of IFN showed anti-PRV activity in PoREC cells, although the antiviral activity of IFN-α was more potent than that of IFN-λ3 in the latter cell type. In conclusion, the current data show that PRV-induced type I and III IFN responses and their antiviral activity depend to a large extent on the epithelial cell type used, and for the first time show that type III IFN displays antiviral activity against PRV in epithelial cells from the respiratory and particularly the intestinal tract.

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“…Xie et al demonstrated that PRV US3 inhibits IFN-I production by degrading IRF3. The results showed that PRV US3 could inhibit host antiviral innate immunity by targeting various host defense mechanisms [ 56 ]. CREB-binding protein (CBP/p300) is a histone acetyltransferase, which has been proved to play an important role in transcriptional regulation.…”

Section: Prv Infection Inhibits Ifn-i Productionmentioning

confidence: 99%

A Tug of War: Pseudorabies Virus and Host Antiviral Innate Immunity

Zhou

et al. 2022

Viruses

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The non-specific innate immunity can initiate host antiviral innate immune responses within minutes to hours after the invasion of pathogenic microorganisms. Therefore, the natural immune response is the first line of defense for the host to resist the invaders, including viruses, bacteria, fungi. Host pattern recognition receptors (PRRs) in the infected cells or bystander cells recognize pathogen-associated molecular patterns (PAMPs) of invading pathogens and initiate a series of signal cascades, resulting in the expression of type I interferons (IFN-I) and inflammatory cytokines to antagonize the infection of microorganisms. In contrast, the invading pathogens take a variety of mechanisms to inhibit the induction of IFN-I production from avoiding being cleared. Pseudorabies virus (PRV) belongs to the family Herpesviridae, subfamily Alphaherpesvirinae, genus Varicellovirus. PRV is the causative agent of Aujeszky's disease (AD, pseudorabies). Although the natural host of PRV is swine, it can infect a wide variety of mammals, such as cattle, sheep, cats, and dogs. The disease is usually fatal to these hosts. PRV mainly infects the peripheral nervous system (PNS) in swine. For other species, PRV mainly invades the PNS first and then progresses to the central nervous system (CNS), which leads to acute death of the host with serious clinical and neurological symptoms. In recent years, new PRV variant strains have appeared in some areas, and sporadic cases of PRV infection in humans have also been reported, suggesting that PRV is still an important emerging and re-emerging infectious disease. This review summarizes the strategies of PRV evading host innate immunity and new targets for inhibition of PRV replication, which will provide more information for the development of effective inactivated vaccines and drugs for PRV.

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Pseudorabies Virus US3 Protein Inhibits IFN-β Production by Interacting With IRF3 to Block Its Activation

Cited by 17 publications

References 53 publications

The Deletion of US3 Gene of Pseudorabies Virus (PRV) ΔgE/TK Strain Induces Increased Immunogenicity in Mice

The Deletion of US3 Gene of Pseudorabies Virus (PRV) ΔgE/TK Strain Induces Increased Immunogenicity in Mice

Pseudorabies virus-induced expression and antiviral activity of type I or type III interferon depend on the type of infected epithelial cell

A Tug of War: Pseudorabies Virus and Host Antiviral Innate Immunity

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