Pseudorabies Virus Inhibits Type I and Type III Interferon-Induced Signaling via Proteasomal Degradation of Janus Kinases

Yuan, Yin; Romero, Nicolás; Favoreel, Herman

doi:10.1128/jvi.00793-21

Cited by 18 publications

(13 citation statements)

References 41 publications

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“…However, although IFN-α significantly inhibited PRV infection, IFN-λ3 did not significantly inhibit PRV infection in PK-15 cells, which corresponded with a very weak induction of ISG expression by IFN-λ3 compared to IFN-α in this cell type. Although the specific receptor chain for type III IFN, IFNLR1, is expressed in PK-15 cells ( 16 ), we found that protein expression levels of this receptor chain are less abundant in this cell type compared to PoREC and IPEC-J2 cells ( Figure 4 ), in line with the apparent weak ISG induction and antiviral activity of type III IFN in PK-15 cells. Interestingly, very recently, another study reported that porcine IFN-λ3 does display antiviral activity against PRV in PK-15 cells ( 12 ).…”

Section: Discussionsupporting

confidence: 56%

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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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Section: Discussionsupporting

confidence: 56%

“…RNA isolation and RT-QPCR were performed as described before ( 16 ).The primers used in this assay are listed in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

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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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“…Treatment with this inhibitor was confirmed to reduce m6A levels by more than 75% ( Figure S4 ). We reported earlier that PRV suppresses IFN signaling by degrading Janus kinases in a proteasome-dependent manner ( Yin et al, 2021 ). Cells were therefore treated with the proteasome inhibitor MG132 to allow detectable expression of ISG transcripts.…”

Section: Resultsmentioning

confidence: 99%

Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex

et al. 2022

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“…Yin et al found that PRV infection can lead to the degradation of JAK1 and Tyk2 through proteasome [ 89 ], inhibiting STAT1 phosphorylation and finally interfering with JAK-STAT signal transduction. However, the early viral protein EP0 does not relate to this inhibition, suggesting that other PRV proteins might recruit other E3 ligases to execute its degradation function.…”

Section: Prv Infection Inhibits Ifn Signaling Pathwaymentioning

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 Inhibits Type I and Type III Interferon-Induced Signaling via Proteasomal Degradation of Janus Kinases

Cited by 18 publications

References 41 publications

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

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

Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex

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

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