scholarly journals DHAV-1 Blocks the Signaling Pathway Upstream of Type I Interferon by Inhibiting the Interferon Regulatory Factor 7 Protein

2021 ◽  
Vol 12 ◽  
Author(s):  
Yalan Lai ◽  
Xiaoyan Xia ◽  
Anchun Cheng ◽  
Mingshu Wang ◽  
Xumin Ou ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Viral Protein ◽  
Interferon Regulatory Factor ◽  
Host Cells ◽  
Luciferase Reporter ◽  
Type I ◽  
Dependent Manner ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 7

Duck hepatitis A virus (DHAV), which mainly infects 1- to 4-week-old ducklings, has a fatality rate of 95% and poses a huge economic threat to the duck industry. However, the mechanism by which DHAV-1 regulates the immune response of host cells is rarely reported. This study examined whether DHAV-1 contains a viral protein that can regulate the innate immunity of host cells and its specific regulatory mechanism, further exploring the mechanism by which DHAV-1 resists the host immune response. In the study, the dual-luciferase reporter gene system was used to screen the viral protein that regulates the host innate immunity and the target of this viral protein. The results indicate that the DHAV-1 3C protein inhibits the pathway upstream of interferon (IFN)-β by targeting the interferon regulatory factor 7 (IRF7) protein. In addition, we found that the 3C protein inhibits the nuclear translocation of the IRF7 protein. Further experiments showed that the 3C protein interacts with the IRF7 protein through its N-terminus and that the 3C protein degrades the IRF7 protein in a caspase 3-dependent manner, thereby inhibiting the IFN-β-mediated antiviral response to promote the replication of DHAV-1. The results of this study are expected to serve as a reference for elucidating the mechanisms of DHAV-1 infection and pathogenicity.

scholarly journals Interferon regulatory factor 7- (IRF7-) mediated immune response affects Newcastle disease virus replication in chicken embryo fibroblasts

2014 ◽  
Vol 62 (4) ◽  
pp. 500-511 ◽  
Author(s):  
Zhaoxiong Wang ◽  
Zhangyong Ning ◽  
Minhua Sun ◽  
Shimin Gao ◽  
Yinfeng Kang ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Replication ◽  
Newcastle Disease ◽  
Chicken Embryo ◽  
Interferon Regulatory Factor ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 7 ◽  
Kinetics Of ◽  
Chicken Embryo Fibroblasts

Interferon regulatory factor 7 (IRF7) is essential for the induction of an antiviral response. Previous studies have shown that virus replication causes the activation or expression of Type I interferon (IFN) in cells, which further activates IFN-stimulated genes (ISGs) to retard virus growth. In this study, after infection of chicken embryo fibroblasts (CEFs) with the lentogenic Newcastle disease virus (NDV) strain LaSota or the velogenic NDV strain GM, the mRNA and protein levels of IRF7 showed a significant increase, and part of the IRF7 protein was translocated from the cytoplasm to the nucleus. In order to further explore the effect of IRF7-mediated innate immune response on the replication of NDV in CEFs, the mRNA levels of IFN-α, IFN-β and STAT1 were measured and the replication kinetics of NDV determined. The results showed that specific siRNA could inhibit the expression of IRF7 and limit the mRNA level of IFN-α, IFN-β and STAT1 and, accordingly, the replication kinetics of both NDVs were enhanced after the inhibition of IRF7. In conclusion, IRF7 is an important nuclear transcription factor for the induction of Type I IFNs during the antiviral response, which can affect the replication of NDV and spread to CEFs in the early phase of viral infection.

scholarly journals 3C Protease of Enterovirus D68 Inhibits Cellular Defense Mediated by Interferon Regulatory Factor 7

2015 ◽  
Vol 90 (3) ◽  
pp. 1613-1621 ◽  
Author(s):  
Zichun Xiang ◽  
Lulu Liu ◽  
Xiaobo Lei ◽  
Zhuo Zhou ◽  
Bin He ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
The United States ◽  
Interferon Regulatory Factor ◽  
Host Cells ◽  
Human Enterovirus ◽  
Type I ◽  
Regulatory Factor ◽  
3C Protease ◽  
Immune Factor ◽  
Interferon Regulatory Factor 7

ABSTRACTHuman enterovirus 68 (EV-D68) is a member of the EV-D species, which belongs to the EV genus of thePicornaviridaefamily. Over the past several years, clusters of EV-D68 infections have occurred worldwide. A recent outbreak in the United States is the largest one associated with severe respiratory illness and neurological complication. Although clinical symptoms are recognized, the virus remains poorly understood. Here we report that EV-D68 inhibits innate antiviral immunity by downregulation of interferon regulatory factor 7 (IRF7), an immune factor with a pivotal role in viral pathogenesis. This process depends on 3Cpro, an EV-D68-encoded protease, to mediate IRF7 cleavage. When expressed in host cells, 3Cprotargets Q167 and Q189 within the constitutive activation domain, resulting in cleavage of IRF7. Accordingly, wild-type IRF7 is fully active. However, IRF7 cleavage abrogated its capacity to activate type I interferon expression and limit replication of EV-D68. Notably, IRF7 cleavage strictly requires the protease activity of 3Cpro. Together, these results suggest that a dynamic interplay between 3Cproand IRF7 may determine the outcome of EV-D68 infection.IMPORTANCEEV-D68 is a globally emerging pathogen, but the molecular basis of EV-D68 pathogenesis is unclear. Here we report that EV-D68 inhibits innate immune responses by targeting an immune factor, IRF7. This involves the 3C protease encoded by EV-D68, which mediates the cleavage of IRF7. These observations suggest that the 3Cpro-IRF7 interaction may represent an interface that dictates EV-D68 infection.

scholarly journals miR-541-3p Promoted Porcine Reproductive and Respiratory Syndrome Virus 2 (PRRSV-2) Replication by Targeting Interferon Regulatory Factor 7

Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 126
Author(s):  
Xibao Shi ◽  
Yuanhao Yang ◽  
Xiaozhuan Zhang ◽  
Xiaobo Chang ◽  
Jing Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
Type I Interferon ◽  
Interferon Regulatory Factor ◽  
Respiratory Syndrome Virus ◽  
Type I ◽  
Regulatory Factor ◽  
Prrs Virus ◽  
Interferon Regulatory Factor 7 ◽  
Host Innate Immune Response ◽  
And Control

Porcine reproductive and respiratory syndrome (PRRS) is a disease caused by PRRS virus (PRRSV), which seriously harms the pig industry. Revealing the mechanism by which PRRSV inhibits immune response will help prevent and control PRRS. Here, we found that PRRSV-2 may hijack host miR-541-3p to inhibit host innate immune response. Firstly, this work showed that miR-541-3p mimics could facilitate the replication of PRRSV-2 and the results of the quantitative real time polymerase chain reaction (qRT-PCR) showed that PRRSV-2 could up-regulate the expression of miR-541-3p in MARC-145 cells. Since previous studies have shown that type I interferon could effectively inhibit the replication of PRRSV-2, the present work explored whether miR-541-3p regulated the expression of type I interferon and found that miR-541-3p could negatively regulate the transcription of type I interferon by targeting interferon regulatory factor 7 (IRF7). More importantly, PRRSV-2 infection could down-regulate the expression of IRF7 and over-expression of IRF7 could down-regulate the replication of PRRSV-2 in MARC-145 cells. In conclusion, PRRSV-2 infection up-regulated the expression of miR-541-3p to promote its replication in MARC-145 cells, since miR-541-3p can negatively regulate the transcription of type I interferon by targeting IRF7.

scholarly journals Loss of Interferon Regulatory Factor 3 in Cells Infected with Classical Swine Fever Virus Involves the N-Terminal Protease, Npro

2005 ◽  
Vol 79 (11) ◽  
pp. 7239-7247 ◽  
Author(s):  
S. Anna La Rocca ◽  
Rebecca J. Herbert ◽  
Helen Crooke ◽  
Trevor W. Drew ◽  
Thomas E. Wileman ◽  
...  
Keyword(s):  
Classical Swine Fever Virus ◽  
Viral Protein ◽  
Sindbis Virus ◽  
Classical Swine Fever ◽  
Interferon Regulatory Factor ◽  
Fever Virus ◽  
Luciferase Reporter ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Infected Cells

ABSTRACT We show that cells infected with the pestivirus classical swine fever virus (CSFV) fail to produce alpha/beta interferon not only following treatment with double-stranded RNA but also after superinfection with a heterologous virus, the alphavirus Sindbis virus, a virus shown to normally induce interferon. We investigated whether the inhibition of interferon synthesis by CSFV involved a block in interferon regulatory factor 3 (IRF3) activity. Cells infected with CSFV exhibited a lack of translocation of green fluorescent protein-IRF3 to the nucleus; however, constitutive shuttling of IRF3 was not blocked, since it could still accumulate in the nucleus in the presence of leptomycin B. Interestingly subcellular fractionation analysis showed that IRF3 was lost from the cytoplasm of infected cells from 18 h postinfection onwards. Using IRF3 promoter-luciferase reporter constructs, we demonstrate that loss of IRF3 was due to an inhibition of transcription of the IRF3 gene in CSFV-infected cells. Further, we investigated which viral protein may be responsible for the inhibition of interferon and loss of IRF3. We used cell lines expressing the CSFV N-terminal protease (Npro) to show that this single viral protein, unique to pestiviruses, inhibited interferon production in response to Sindbis virus. In addition to being lost from CSFV-infected cells, IRF3 was lost from Npro-expressing cells. The results demonstrate a novel viral evasion of innate host defenses, where interferon synthesis is prevented by inhibiting transcription of IRF3 in CSFV-infected cells.

scholarly journals Sequential Interferon β-Cisplatin Treatment Enhances the Surface Exposure of Calreticulin in Cancer Cells via an Interferon Regulatory Factor 1-Dependent Manner

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 643 ◽  
Author(s):  
Pei-Ming Yang ◽  
Yao-Yu Hsieh ◽  
Jia-Ling Du ◽  
Shih-Chieh Yen ◽  
Chien-Fu Hung
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Interferon Regulatory Factor ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Regulatory Factor ◽  
Interferon Β ◽  
Interferon Regulatory Factor 1 ◽  
Molecular Determinants

Immunogenic cell death (ICD) refers to a unique form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Accumulating evidence indicates that the efficacy of conventional anticancer agents relies on not only their direct cytostatic/cytotoxic effects but also the activation of antitumor ICD. Common anticancer ICD inducers include certain chemotherapeutic agents (such as anthracyclines, oxaliplatin, and bortezomib), radiotherapy, photodynamic therapy (PDT), and oncolytic virotherapies. However, most chemotherapeutic reagents are inefficient or fail to trigger ICD. Therefore, better understanding on the molecular determinants of chemotherapy-induced ICD will help in the development of more efficient combinational anticancer strategies through converting non- or relatively weak ICD inducers into bona fide ICD inducers. In this study, we found that sequential, but not concurrent, treatment of cancer cells with interferon β (IFNβ), a type I IFN, and cisplatin (an inefficient ICD inducer) can enhance the expression of ICD biomarkers in cancer cells, including surface translocation of an endoplasmic reticulum (ER) chaperone, calreticulin (CRT), and phosphorylation of the eukaryotic translation initiation factor alpha (eIF2α). These results suggest that exogenous IFNβ may activate molecular determinants that convert cisplatin into an ICD inducer. Further bioinformatics and in vitro experimental analyses found that interferon regulatory factor 1 (IRF1) acted as an essential mediator of surface CRT exposure by sequential IFNβ-cisplatin combination. Our findings not only help to design more effective combinational anticancer therapy using IFNβ and cisplatin, but also provide a novel insight into the role of IRF1 in connecting the type I IFN responses and ICD.

scholarly journals Interferon regulatory factor 7 (IRF7) represents a link between inflammation and fibrosis in the pathogenesis of systemic sclerosis

2019 ◽  
Vol 78 (11) ◽  
pp. 1583-1591 ◽  
Author(s):  
Minghua Wu ◽  
Brian Skaug ◽  
Xiongjie Bi ◽  
Tingting Mills ◽  
Gloria Salazar ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Interferon Regulatory Factor ◽  
Dermal Fibroblasts ◽  
Type I ◽  
Type I Ifn ◽  
Hydroxyproline Content ◽  
Regulatory Factor ◽  
Dermal Fibrosis ◽  
Interferon Regulatory Factor 7

ObjectivesThere is considerable evidence that implicates dysregulation of type I interferon signalling (or type I IFN signature) in the pathogenesis of systemic sclerosis (SSc). Interferon regulatory factor 7 (IRF7) has been recognised as a master regulator of type I IFN signalling. The objective of this study was to elucidate the role of IRF7 in dermal fibrosis and SSc pathogenesis.MethodsSSc and healthy control skin biopsies were investigated to determine IRF7 expression and activation. The role of IRF7 in fibrosis was investigated using IRF7 knockout (KO) mice in the bleomycin-induced and TSK/+mouse models. In vitro experiments with dermal fibroblasts from patients with SSc and healthy controls were performed.ResultsIRF7 expression was significantly upregulated and activated in SSc skin tissue and explanted SSc dermal fibroblasts compared with unaffected, matched controls. Moreover, IRF7 expression was stimulated by IFN-α in dermal fibroblasts. Importantly, IRF7 co-immunoprecipitated with Smad3, a key mediator of transforming growth factor (TGF)-β signalling, and IRF7 knockdown reduced profibrotic factors in SSc fibroblasts. IRF7 KO mice demonstrated attenuated dermal fibrosis and inflammation compared with wild-type mice in response to bleomycin. Specifically, hydroxyproline content, dermal thickness as well as Col1a2, ACTA2 and interleukin-6 mRNA levels were significantly attenuated in IRF7 KO mice skin tissue. Furthermore, IRF7 KO in TSK/+mice attenuated hydroxyproline content, subcutaneous hypodermal thickness, Col1a2 mRNA as well as α-smooth muscle actin and fibronectin expression.ConclusionsIRF7 is upregulated in SSc skin, interacts with Smad3 and potentiates TGF-β-mediated fibrosis, and therefore may represent a promising therapeutic target in SSc.

scholarly journals Fine-Tuning of the RIG-I-Like Receptor/Interferon Regulatory Factor 3-Dependent Antiviral Innate Immune Response by the Glycogen Synthase Kinase 3/β-Catenin Pathway

2015 ◽  
Vol 35 (17) ◽  
pp. 3029-3043 ◽  
Author(s):  
Kashif Aziz Khan ◽  
Florence Dô ◽  
Alexandre Marineau ◽  
Priscilla Doyon ◽  
Jean-François Clément ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Glycogen Synthase ◽  
Es Cells ◽  
Interferon Regulatory Factor ◽  
Innate Immune ◽  
Regulatory Factor ◽  
Gsk 3Β ◽  
Antiviral Innate Immunity

Induction of an antiviral innate immune response relies on pattern recognition receptors, including retinoic acid-inducible gene 1-like receptors (RLR), to detect invading pathogens, resulting in the activation of multiple latent transcription factors, including interferon regulatory factor 3 (IRF3). Upon sensing of viral RNA and DNA, IRF3 is phosphorylated and recruits coactivators to induce type I interferons (IFNs) and selected sets of IRF3-regulated IFN-stimulated genes (ISGs) such as those for ISG54 (Ifit2), ISG56 (Ifit1), and viperin (Rsad2). Here, we used wild-type, glycogen synthase kinase 3α knockout (GSK-3α−/−), GSK-3β−/−, and GSK-3α/β double-knockout (DKO) embryonic stem (ES) cells, as well as GSK-3β−/−mouse embryonic fibroblast cells in which GSK-3α was knocked down to demonstrate that both isoforms of GSK-3, GSK-3α and GSK-3β, are required for this antiviral immune response. Moreover, the use of two selective small-molecule GSK-3 inhibitors (CHIR99021 and BIO-acetoxime) or ES cells reconstituted with the catalytically inactive versions of GSK-3 isoforms showed that GSK-3 activity is required for optimal induction of antiviral innate immunity. Mechanistically, GSK-3 isoform activation following Sendai virus infection results in phosphorylation of β-catenin at S33/S37/T41, promoting IRF3 DNA binding and activation of IRF3-regulated ISGs. This study identifies the role of a GSK-3/β-catenin axis in antiviral innate immunity.

The role of interferon regulatory factor 7 in the pathogenicity and immunogenicity of rabies virus in a mouse model

2021 ◽  
Vol 102 (10) ◽  
Author(s):  
Caiqian Wang ◽  
Lei Lv ◽  
Qiong Wu ◽  
Zongmei Wang ◽  
Zhaochen Luo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rabies Virus ◽  
Plasma Cells ◽  
Early Stage ◽  
Interferon Regulatory Factor ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 7

Rabies is a zoonotic disease caused by the rabies virus (RABV). RABV can lead to fatal encephalitis and is still a serious threat in most parts of the world. Interferon regulatory factor 7 (IRF7) is the main transcriptional regulator of type I IFN, and it is crucial for the induction of IFNα/β and the type I IFN-dependent immune response. In this study, we focused on the role of IRF7 in the pathogenicity and immunogenicity of RABV using an IRF7-/- mouse model. The results showed that the absence of IRF7 made mice more susceptible to RABV, because IRF7 restricted the replication of RABV in the early stage of infection. IRF7 deficiency affected the recruitment of plasmacytoid dendritic cells to the draining lymph nodes (dLNs), reduced the production of type I IFN and expression of IFN-stimulated genes. Furthermore, we found that the ability to produce specific RABV-neutralizing antibody was impaired in IRF7-/- mice. Consistently, IRF7 deficiency affected the recruitment of germinal-centre B cells to dLNs, and the generation of plasma cells and RABV-specific antibody secreting cells. Moreover, the absence of IRF7 downregulated the induction of IFN-γ and reduced type 1 T helper cell (Th1)-dependent antibody production. Collectively, our findings demonstrate that IRF7 promotes humoral immune responses and compromises the pathogenicity of RABV in a mouse model.

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