Pseudorabies Virus DNA Polymerase Processivity Factor UL42 Inhibits Type I IFN Response by Preventing ISGF3-ISRE Interaction

2021 ◽  
pp. ji2001306
Author(s):  
Rui Zhang ◽  
Shifan Chen ◽  
Ying Zhang ◽  
Mengdong Wang ◽  
Chao Qin ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Pseudorabies Virus ◽  
Type I ◽  
Type I Ifn ◽  
Processivity Factor

scholarly journals Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I Interferon Receptor 1 and Antagonizes the Alpha Interferon Response

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Rui Zhang ◽  
Aotian Xu ◽  
Chao Qin ◽  
Qiong Zhang ◽  
Shifan Chen ◽  
...  
Keyword(s):  
Pseudorabies Virus ◽  
Type I Interferon ◽  
Antiviral Drug ◽  
Ectopic Expression ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Lysosomal Degradation ◽  
Independent Manner ◽  
Strong Inhibitor

ABSTRACT Alphaherpesviruses that establish persistent infections rely partly on their ability to evade host antiviral responses, notably the type I interferon (IFN) response. However, the mechanisms employed by alphaherpesviruses to avoid this response are not well understood. Pseudorabies virus (PRV) is an economically important pathogen and a useful model system for studying alphaherpesvirus biology. To identify PRV proteins that antagonize type I IFN signaling, we performed a screen by using an IFN-stimulated response element reporter in the swine cell line CRL. Unexpectedly, we identified the dUTPase UL50 as a strong inhibitor. We confirmed that UL50 has the ability to inhibit type I IFN signaling by performing ectopic expression of UL50 in cells and deletion of UL50 in PRV. Mechanistically, UL50 impeded type I IFN-induced STAT1 phosphorylation, likely by accelerating lysosomal degradation of IFN receptor 1 (IFNAR1). In addition, this UL50 activity was independent of its dUTPase activity and required amino acids 225 to 253 in the C-terminal region. The UL50 encoded by herpes simplex virus 1 (HSV-1) also possessed similar activity. Moreover, UL50-deleted PRV was more susceptible to IFN than UL50-proficient PRV. Our results suggest that in addition to its dUTPase activity, the UL50 protein of alphaherpesviruses possesses the ability to suppress type I IFN signaling by promoting lysosomal degradation of IFNAR1, thereby contributing to immune evasion. This finding reveals UL50 as a potential antiviral target. IMPORTANCE Alphaherpesviruses can establish lifelong infections and cause many diseases in humans and animals. Pseudorabies virus (PRV) is a swine alphaherpesvirus that threatens pig production. Using PRV as a model, we found that this alphaherpesvirus could utilize its encoded dUTPase UL50 to induce IFNAR1 degradation and inhibit type I IFN signaling in an enzymatic activity-independent manner. Our finding reveals a mechanism employed by an alphaherpesvirus to evade the immune response and indicates that UL50 is an important viral protein in pathogenesis and is a potential target for antiviral drug development.

Targeting the pseudorabies virus DNA polymerase processivity factor UL42 by RNA interference efficiently inhibits viral replication

2016 ◽  
Vol 132 ◽  
pp. 219-224 ◽  
Author(s):  
Yi-Ping Wang ◽  
Li-Ping Huang ◽  
Wen-Juan Du ◽  
Yan-Wu Wei ◽  
Hong-Li Wu ◽  
...  
Keyword(s):  
Rna Interference ◽  
Viral Replication ◽  
Dna Polymerase ◽  
Pseudorabies Virus ◽  
Processivity Factor

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Jingying Xie ◽  
Xiangbo Zhang ◽  
Lei Chen ◽  
Yingjie Bi ◽  
Adi Idris ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Neurological Disorders ◽  
Pseudorabies Virus ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral Immune Response ◽  
Depth Study ◽  
Restricted Type ◽  
Viral Factor ◽  
Novel Strategy

Pseudorabies virus is a typical swine alphaherpesvirus, which can cause obvious neurological disorders and reproductive failure in pigs. It is capable of evading host antiviral immune response. However, the mechanism by which many PRV proteins assist the virus to evade innate immunity is not fully understood. This study identified PRV US3 protein as a crucial antagonistic viral factor that represses interferon beta (IFN-β) expression. A in-depth study showed that US3 protein restricted type I IFN production by targeting interferon regulatory factor 3 (IRF3), a key molecule required for type I IFN induction. Additionally, US3 protein interacted with IRF3, degraded its protein expression to block the phosphorylation of IRF3. These findings suggested a novel strategy utilized by PRV to inhibit IFN-β production and escape the host innate immunity.

The pseudorabies virus DNA polymerase processivity factor UL42 exists as a monomer in vitro and in vivo

2016 ◽  
Vol 161 (4) ◽  
pp. 1027-1031
Author(s):  
Yi-Ping Wang ◽  
Li-Ping Huang ◽  
Wen-Juan Du ◽  
Yan-Wu Wei ◽  
De-Li Xia ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Pseudorabies Virus ◽  
Processivity Factor

scholarly journals Type I IFN Modulates the Immune Response Induced by DNA Vaccination to Pseudorabies Virus Glycoprotein C

Virology ◽  
2001 ◽  
Vol 286 (1) ◽  
pp. 197-205 ◽  
Author(s):  
Daniela Tudor ◽  
Sabine Riffault ◽  
Charles Carrat ◽  
François Lefèvre ◽  
Marielle Bernoin ◽  
...  
Keyword(s):  
Immune Response ◽  
Pseudorabies Virus ◽  
Dna Vaccination ◽  
Type I ◽  
Type I Ifn ◽  
Glycoprotein C ◽  
Virus Glycoprotein

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 13
Author(s):  
Martin Hyrcza ◽  
Mario Ostrowski ◽  
Sandy Der
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Hiv Infection ◽  
Gene Transcription ◽  
Sendai Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

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