IRF7 Exacerbates Candida albicans Infection by Compromising CD209-Mediated Phagocytosis and Autophagy-Mediated Killing in Macrophages.

IFN regulatory factor 7 (IRF7) exerts anti-infective effects by promoting the production of IFNs in various bacterial and viral infections, but its role in highly morbid and fatal Candida albicans infections is unknown. We unexpectedly found that Irf7 gene expression levels were significantly upregulated in tissues or cells after C. albicans infection in humans and mice and that IRF7 actually exacerbates C. albicans infection in mice independent of its classical function in inducing IFNs production. Compared to controls, Irf7-/- mice showed stronger phagocytosis of fungus, upregulation of C-type lectin receptor CD209 expression, and enhanced P53-AMPK-mTOR-mediated autophagic signaling in macrophages after C. albicans infection. The administration of the CD209-neutralizing Ab significantly hindered the phagocytosis of Irf7-/- mouse macrophages, whereas the inhibition of p53 or autophagy impaired the killing function of these macrophages. Thus, IRF7 exacerbates C. albicans infection by compromising the phagocytosis and killing capacity of macrophages via regulating CD209 expression and p53-AMPK-mTOR-mediated autophagy, respectively. This finding reveals a novel function of IRF7 independent of its canonical IFNs production and its unexpected role in enhancing fungal infections, thus providing more specific and effective targets for antifungal therapy.

SGIV VP82 inhibits the interferon response by degradation of IRF3 and IRF7.

During virus-host co-evolution, viruses have developed multiple strategies to dampen IFN response and prevent its antiviral activity in host cells. To date, the interactions between host IFN response and the immune evasion strategies exploited by fish iridoviruses still remain largely uncertain. Here, a potential immune evasion protein candidate of Singapore grouper iridovirus (SGIV), VP82 (encoded by SGIV ORF82) was screened and its roles during viral replication were investigated in detail. Firstly, VP82 overexpression dramatically decreased IFN or ISRE promoter activity and the transcription levels of IFN stimulated genes (ISGs) stimulated by grouper cyclic GMP-AMP synthase (EccGAS)/stimulator of interferon genes (EcSTING), TANK-binding kinase 1 (EcTBK1), IFN regulatory factor 3 (EcIRF3)and EcIRF7. Secondly, Co-IP assays indicated that VP82 interacted with EcIRF3 and EcIRF7, but not EcSTING and EcTBK1, which was consistent with the co-localization between VP82 and EcIRF3 or EcIRF7. Furthermore, VP82 promoted the degradation of EcIRF3 and EcIRF7 in a dose-dependent manner via the autophagy pathway. Finally, VP82 overexpression accelerated SGIV replication, evidenced by the increased transcriptions of viral core genes and viral production. Moreover, the antiviral action of EcIRF3 or EcIRF7 was significantly depressed in VP82 overexpressed cells. Together, VP82 was speculated to exert crucial roles for SGIV replication by inhibiting the IFN response via the degradation of IRF3 and IRF7. Our findings provided new insights into understanding the immune evasion strategies utilized by fish iridovirus through IFN regulation.

Non-transcriptional IRF7 interacts with NF-κB to inhibit viral inflammation.

Interferon (IFN) regulatory factors (IRF) are key transcription factors in cellular antiviral responses. IRF7, a virus-inducible IRF, expressed primarily in myeloid cells, is required for transcriptional induction of interferon α and antiviral genes. IRF7 is activated by virus-induced phosphorylation in the cytoplasm, leading to its translocation to the nucleus for transcriptional activity. Here, we revealed a nontranscriptional activity of IRF7 contributing to its antiviral functions. IRF7 interacted with the pro-inflammatory transcription factor NF-κB-p65 and inhibited the induction of inflammatory target genes. Using knockdown, knockout, and overexpression strategies, we demonstrated that IRF7 inhibited NF-κB-dependent inflammatory target genes, induced by virus infection or toll-like receptor stimulation. A mutant IRF7, defective in transcriptional activity, interacted with NF-κB-p65 and suppressed NF-κB-induced gene expression. A single-action IRF7 mutant, active in anti-inflammatory function, but defective in transcriptional activity, efficiently suppressed Sendai virus and murine hepatitis virus replication. We, therefore, uncovered an anti-inflammatory function for IRF7, independent of transcriptional activity, contributing to the antiviral response of IRF7.

Melanoma Derived Exosomes Amplify Radiotherapy Induced Abscopal Effect via IRF7/I-IFN Axis in Macrophages.

Radiotherapy (RT) can induce tumor regression outside the irradiation field, known as the abscopal effect. However, the detailed underlying mechanisms remain largely unknown. A tumor-bearing mouse model is successfully constructed by inducing both subcutaneous tumors and lung metastases. Single-cell RNA sequencing, immunofluorescence, and flow cytometry are performed to explore the regulation of tumor microenvironment (TME) by RT. A series of in vitro assays, including luciferase reporter, RNA Pulldown, and fluorescent in situ hybridization (FISH) assays, are performed to evaluate the detailed mechanism of the abscopal effect. In addition, in vivo assays are performed to investigate combination therapy strategies for enhancing the abscopal effect. The results showed that RT significantly inhibited localized tumor and lung metastasis progression and improved the TME. Mechanistically, RT promoted the release of tumor-derived exosomes carrying circPIK3R3, which is taken up by macrophages. circPIK3R3 promoted Type I interferon (I-IFN) secretion and M1 polarization via the miR-872-3p/IRF7 axis. Secreted I-IFN activated the JAK/STAT signaling pathway in CD8+ T cells, and promoted IFN-γ and GZMB secretion. Together, the study shows that tumor-derived exosomes promote I-IFN secretion via the circPIK3R3/miR-872-3p/IRF7 axis in macrophages and enhance the anti-tumor immune response of CD8+ T cells.

IRF7: role and regulation in immunity and autoimmunity.

Interferon regulatory factor (IRF) 7 was originally identified as master transcriptional factor that produced IFN-I and regulated innate immune response, subsequent studies have revealed that IRF7 performs a multifaceted and versatile functions in multiple biological processes. In this review, we provide a comprehensive overview on the current knowledge of the role of IRF7 in immunity and autoimmunity. We focus on the latest regulatory mechanisms of IRF7 in IFN-I, including signaling pathways, transcription, translation, and post-translational levels, the dimerization and nuclear translocation, and the role of IRF7 in IFN-III and COVID-19. In addition to antiviral immunity, we also discuss the role and mechanism of IRF7 in autoimmunity, and the further research will expand our understanding of IRF7.

Mice Plasmacytoid Dendritic Cells Were Activated by Lipopolysaccharides Through Toll-Like Receptor 4/Myeloid Differentiation Factor 2.

Plasmacytoid dendritic cells (pDCs) are known to respond to viral infections. However, the activation of pDCs by bacterial components such as lipopolysaccharides (LPS) has not been well studied. Here, we found that pDCs, conventional dendritic cells (cDCs), and B cells express high levels of toll-like receptor 4 (TLR4), a receptor for LPS. Moreover, LPS could effectively bind to not only cDCs but also pDCs and B cells. Intraperitoneal administration of LPS promoted activation of splenic pDCs and cDCs. LPS treatment led to upregulation of interferon regulatory factor 7 (IRF7) and induced production of interferon-alpha (IFN-α) in splenic pDCs. Furthermore, LPS-dependent upregulation of co-stimulatory molecules in pDCs did not require the assistance of other immune cells, such as cDCs. However, the production levels of IFN-α were decreased in cDC-depleted splenocytes, indicating that cDCs may contribute to the enhancement of IFN-α production in pDCs. Finally, we showed that activation of pDCs by LPS requires the TLR4 and myeloid differentiation factor 2 (MD2) signaling pathways. Thus, these results demonstrate that the gram-negative component LPS can directly stimulate pDCs via TLR4/MD2 stimulation in mice.

Myeloid neddylation targets IRF7 and promotes host innate immunity against RNA viruses.

Neddylation, an important type of post-translational modification, has been implicated in innate and adapted immunity. But the role of neddylation in innate immune response against RNA viruses remains elusive. Here we report that neddylation promotes RNA virus-induced type I IFN production, especially IFN-α. More importantly, myeloid deficiency of UBA3 or NEDD8 renders mice less resistant to RNA virus infection. Neddylation is essential for RNA virus-triggered activation of Ifna gene promoters. Further exploration has revealed that mammalian IRF7undergoes neddylation, which is enhanced after RNA virus infection. Even though neddylation blockade does not hinder RNA virus-triggered IRF7 expression, IRF7 mutant defective in neddylation exhibits reduced ability to activate Ifna gene promoters. Neddylation blockade impedes RNA virus-induced IRF7 nuclear translocation without hindering its phosphorylation and dimerization with IRF3. By contrast, IRF7 mutant defective in neddylation shows enhanced dimerization with IRF5, an Ifna repressor when interacting with IRF7. In conclusion, our data demonstrate that myeloid neddylation contributes to host anti-viral innate immunity through targeting IRF7 and promoting its transcriptional activity.

IRF7-Associated Immunophenotypes Have Dichotomous Responses to Virus/Allergen Coexposure and OM-85-Induced Reprogramming.

High risk for virus-induced asthma exacerbations in children is associated with an IRF7lo immunophenotype, but the underlying mechanisms are unclear. Here, we applied a Systems Biology approach to an animal model comprising rat strains manifesting high (BN) versus low susceptibility (PVG) to experimental asthma, induced by virus/allergen coexposure, to elucidate the mechanism(s)-of-action of the high-risk asthma immunophenotype. We also investigated potential risk mitigation via pretreatment with the immune training agent OM-85. Virus/allergen coexposure in low-risk PVG rats resulted in rapid and transient airways inflammation alongside IRF7 gene network formation. In contrast, responses in high-risk BN rats were characterized by severe airways eosinophilia and exaggerated proinflammatory responses that failed to resolve, and complete absence of IRF7 gene networks. OM-85 had more profound effects in high-risk BN rats, inducing immune-related gene expression changes in lung at baseline and reducing exaggerated airway inflammatory responses to virus/allergen coexposure. In low-risk PVG rats, OM-85 boosted IRF7 gene networks in the lung but did not alter baseline gene expression or cellular influx. Distinct IRF7-associated asthma risk immunophenotypes have dichotomous responses to virus/allergen coexposure and respond differentially to OM-85 pretreatment. Extrapolating to humans, our findings suggest that the beneficial effects OM-85 pretreatment may preferentially target those in high-risk subgroups.

Quorum sensing governs collective dendritic cell activation in vivo.

Dendritic cell (DC) activation by viral RNA sensors such as TLR3 and MDA-5 is critical for initiating antiviral immunity. Optimal DC activation is promoted by type I interferon (IFN) signaling which is believed to occur in either autocrine or paracrine fashion. Here, we show that neither autocrine nor paracrine type I IFN signaling can fully account for DC activation by poly(I:C) in vitro and in vivo. By controlling the density of type I IFN-producing cells in vivo, we establish that instead a quorum of type I IFN-producing cells is required for optimal DC activation and that this process proceeds at the level of an entire lymph node. This collective behavior, governed by type I IFN diffusion, is favored by the requirement for prolonged cytokine exposure to achieve DC activation. Furthermore, collective DC activation was found essential for the development of innate and adaptive immunity in lymph nodes. Our results establish how collective rather than cell-autonomous processes can govern the initiation of immune responses.

Porcine Epidemic Diarrhea Virus Membrane Protein Interacted with IRF7 to Inhibit Type I IFN Production during Viral Infection.

Porcine epidemic diarrhea virus (PEDV) is a highly pathogenic porcine enteropathogenic coronavirus causing severe enteritis and lethal watery diarrhea in piglets. PEDV infection suppresses the synthesis of type I IFN, and multiple viral proteins of PEDV have been shown to target the adaptors of innate immune pathways to inhibit type I IFN production. In this study, we identified PEDV membrane (M) protein as a new antagonist of type I IFN production in both human embryonic kidney HEK293T cells and porcine kidney PK-15 cells and determined the antagonistic mechanism used by M protein to target IFN regulatory factor 7 (IRF7), an important regulator of type I IFN production. IRF7 is phosphorylated and activated by TBK1 and IKKε in response to viral infection. We found that PEDV M protein interacted with the inhibitory domain of IRF7 and significantly suppressed TBK1/IKKε-induced IRF7 phosphorylation and dimerization of IRF7, leading to the decreased expression of type I IFN, although it did not affect the interaction between TBK1/IKKε and IRF7. As expected, overexpression of M protein significantly increased PEDV replication in porcine cells. The M proteins of both epidemic PEDV strains and vaccine strain showed similar antagonistic effect on type I IFN production, and the 1-55 region of M protein was essential for disruption of IRF7 function by interacting with IRF7. Taken together, our data identified a new, to our knowledge, IFN antagonist of PEDV, as well as a novel, to our knowledge, antagonistic mechanism evolved by PEDV to inhibit type I IFN production.

MEKK3 activates IRF7 to trigger a potent type I interferon induction in response to TLR7/9 signaling.

Interferon regulatory factor 7 (IRF7) is a crucial regulator of type I interferons (IFNs) against pathogen infections and plays a significant role in the endosomal Toll-like receptor signaling (namely, TLR7 and TLR9) in plasmacytoid dendritic cells (pDCs). In this study, we identify MEKK3, one of the MAP3K kinase, as a potent stimulator of IRF7 upon cellular activation of the TLR7/9 signaling pathways to induce various type I IFNs. The knockdown of MEKK3 in vivo substantially impairs type I IFN induction and increases susceptibility to HSV-1 infection in mice. Overexpression of MEKK3 significantly activates IRF7 to trigger strong induction of type I IFNs, while cells deficient in MEKK3 expression show abrogated innate immune responses to TLR7/TLR9 ligands stimulation. We confirmed that the IFNs' induction is due to a MEKK3 and IRF7 interaction; it leads to the phosphorylation of IRF7 at multiple sites. Moreover, endogenous MEKK3 can bind and phosphorylate IRF7 after TLR9 activation by its specific ligand CpG DNA. It is the first time to report the role of MEKK3 on type I IFN, which indicates crosstalk between MAP3K activation and type I IFNs' induction in the endosomal Toll-like receptor pathways.

NMI Facilitates Influenza A Virus Infection by Promoting Degradation of IRF7 through TRIM21.

Acute respiratory infections caused by influenza A virus (IAV) spread widely and lead to substantial morbidity and mortality. Host cell induction of type I interferon (IFN-I) plays a fundamental role in eliminating the virus during the innate antiviral response. The potential role of N-myc and STAT interactor (NMI) and its underlying mechanisms of action during IAV infection, however, remain elusive. In this study, we found that the expression of NMI increased after IAV infection. Nmi-knockout mice infected with IAV displayed increased survival rate, decreased weight loss, lower viral replication, and attenuated lung inflammation when compared with wild-type mice. Deficiency of NMI promoted the production of IFN-I and IFN-stimulated genes in vivo and in vitro. Reduced levels of NMI also resulted in an increase of the expression of IFN regulator factor (IRF) 7. Further studies have revealed that NMI could interact with IRF7 after IAV infection, and this interaction involved its NID1 and NID2 domain. In addition, NMI facilitated ubiquitination and proteasome-dependent degradation of IRF7 through recruitment of the E3 ubiquitin ligase TRIM21 (tripartite motif-containing 21) to limit the IAV-triggered innate immunity. Our findings reveal a clearer understanding of the role of NMI in regulating the host innate antiviral response and provide a potential therapeutic target for controlling IAV infection.

Chicken interferon regulatory factor 7 (IRF7) can control ALV-J virus infection by triggering type I interferon production through affecting genes related with innate immune signaling pathway.

In order to breed new birds with strong disease resistance, it is necessary to first understand the mechanism of avian antiviral response. Interferon regulatory factor 7 (IRF7) is not only a member of type I interferons (IFNs) regulatory factor (IRFs) family, but also a major regulator of the IFN response in mammals. However, whether IRF7 is involved in the host innate immune response remains unclear in poultry, due to the absence of IRF3. Here, we first observed by HE stains that with the increase of the time of ALV-J challenge, the thymus was obviously loose and swollen, the arrangement of liver cell was disordered, and the bursa of fabricius formed vacuolated. Real-time PCR detection showed that the expression level of IRF7 gene and related immune genes in ALV-J group was significantly higher than that in control group (P < 0.05). To further study the role of chicken IRF7 during avian leukosis virus subgroup J (ALV-J) infection, we constructed an induced IRF7 overexpression and interfered chicken embryo fibroblasts (CEFs) cell and performed in vitro infection using low pathogenic ALV-J and virus analog poly(I:C). In ALV-J and poly(I:C) stimulated CEFs cells, the expression level of STAT1, IFN-α, IFN-ß, TLR3 and TLR7 were increased after IRF7 overexpressed, while the results were just the opposite after IRF7 interfered, which indicating that IRF7 may be associated with Toll-like receptor signaling pathway and JAK-STAT signaling pathway. These findings suggest that chicken IRF7 is an important regulator of IFN and is involved in chicken anti-ALV-J innate immunity.

Interferon regulatory factor 7 contributes to the host response during Vibrio harveyi infection in the golden pompano Trachinotus ovatus.

Vibrio harveyi is regarded as serious pathogen for marine fishes. However, host defense mechanisms involved in V. harveyi infection remain incompletely defined. The transcription factor IFN regulatory factor 7 (IRF7) is largely associated with host defense against viral infections, and the role of IRF7 during V. harveyi infection in fish has not been well illuminated previously. In this study, IRF7 from golden pompano (Trachinotus ovatus) was characterized (TroIRF7). The TroIRF7 gene is 1323 bp, which encodes 440 amino acid residues. Multiple amino acid alignments of TroIRF7 shows 30.37%-80.18% identity with other fish IRF7s, including Epinephelus coioides (80.18%), Larimichthys crocea (79.72%), Collichthys lucidus (79.26%), Miichthys miiuy (79.26%), Channa argus (78.77%), Cynoglossus semilaevis (72.67%), and Gadus morhua (65.23%). Like other IRF7s, TroIRF7 also contains 3 conserved domains: an N-terminal DNA-binding domain (DBD), an IRF association domain (IAD), and a C-terminal serine-rich domain (SRD). In the DBD, 4-5 conserved tryptophans were observed, which is a characteristic unique to all fish IRF7 members. TroIRF7 was constitutively expressed, with high levels in gill, head kidney, spleen, skin, and intestine. V. harveyi infection-induced TroIRF7 transcripts significantly up-regulation and translocation to the nucleus. TroIRF7 overexpression promote the fish to inhibit the replication of V. harveyi. And TroIRF7 knockdown led to decreased bacterial clearance in fish tissue. Furthermore, over-expression of TroIRF7 resulted in an increased production of interferon a3 and IFN signaling molecule in the spleen, suggesting that V. harveyi activates the IRF7- IFN pathway. These results suggest that TroIRF7 is an important component of immune responses against V. harveyi infection.

Interferon Regulatory Factors IRF1 and IRF7 Directly Regulate Gene Expression in Bats in Response to Viral Infection.

Bat cells and tissue have elevated basal expression levels of antiviral genes commonly associated with interferon alpha (IFNα) signaling. Here, we show Interferon Regulatory Factor 1 (IRF1), 3, and 7 levels are elevated in most bat tissues and that, basally, IRFs contribute to the expression of type I IFN ligands and high expression of interferon regulated genes (IRGs). CRISPR knockout (KO) of IRF 1/3/7 in cells reveals distinct subsets of genes affected by each IRF in an IFN-ligand signaling-dependent and largely independent manner. As the master regulators of innate immunity, the IRFs control the kinetics and maintenance of the IRG response and play essential roles in response to influenza A virus (IAV), herpes simplex virus 1 (HSV-1), Melaka virus/Pteropine orthoreovirus 3 Melaka (PRV3M), and Middle East respiratory syndrome-related coronavirus (MERS-CoV) infection. With its differential expression in bats compared to that in humans, this highlights a critical role for basal IRF expression in viral responses and potentially immune cell development in bats with relevance for IRF function in human biology.

BVDV-1 induces interferon-beta gene expression through a pathway involving IRF1, IRF7, and NF-κB activation.

The bovine viral diarrhea virus (BVDV-1) is a pathogen with the capacity to modulate the interferon type I system. To further investigate the effects of BVDV-1 on the production of the immune response, the Madin-Darby bovine kidney cell line was infected with the cytopathic CH001 field isolate of BVDV-1, and the IFNbeta expression profiles were analyzed. The results showed that cpBVDV-1 was able to induce the production of IFNbeta in a way similar to polyinosinic-polycytidylic acid, but with less intensity. Interestingly, all cpBVDV-1 activities were blocked by pharmacological inhibitors of the IRF-1, IRF-7, and NF-κB signaling pathway, and the level of IFNbeta decreased at the level of transcript and protein. These results, together with in silico analyses showing the presence of several regulatory consensus target motifs, suggest that cpBVDV-1 regulates IFNbeta expression in bovines through the activation of several key transcription factors. Collectively, the results suggest that during cpBVDV-1 infection, cross talk is evident between various signaling pathways involved in transcriptional activation of IFNbeta in cattle.

Porcine deltacoronavirus nucleocapsid protein species-specifically suppressed IRF7-induced type I interferon production via ubiquitin-proteasomal degradation pathway.

Coronaviruses (CoVs) is showing obvious interspecies transmission, such as the SARS-CoV, MERS-CoV and SARS-CoV-2. Here, the emerging porcine deltacoronavirus (PDCoV) strain, isolated from Shanghai, China, broadly infects porcine, human and chicken cells in vitro. Previously studies by our group and others have confirmed that PDCoV nucleocapsid (N) protein performs an important role in antagonizing retinoic acid-induced gene I-like receptor (RLR) activation. However, the mechanism of PDCoV N protein suppressing porcine type I IFN production remains unclear, especially the downstream of porcine RLR signaling pathway. In the present study, porcine IRF7 (poIRF7) was identified as the interaction protein of PDCoV N protein through LC-MS/MS. The poIRF7 (268-487aa) was the key region of binding PDCoV N protein. Although IRF7 is a conserved functional protein in species, the PDCoV N protein has been confirmed to interact with only poIRF7 and significantly decrease poIRF7-induced type I IFN production, but not human or chicken IRF7. Furthermore, PDCoV N protein can promote poIRF7 degradation via the ubiquitin-proteasome pathway, which directly increased the K6, K11, and K29-linked polyubiquitination of poIRF7. Lysine 359 of poIRF7 was a key site in PDCoV N protein inducing poIRF7 degradation. Taken together, our results reveal a novel mechanism that PDCoV N protein could species-specifically interact with poIRF7 and then promote its degradation to suppress porcine type I IFN production. The novel findings provide a new insight into PDCoV and other zoonotic coronavirus evading the innate immune response of different species.

Interferon Regulatory Factor 7 Attenuates Chronic Gammaherpesvirus Infection.

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections and are associated with a variety of malignancies, including lymphomas. Interferon regulatory factor 7 (IRF-7) is an innate immune transcription factor that restricts acute replication of diverse viruses, including murine gammaherpesvirus 68 (MHV68). Importantly, very little is known about the role of IRF-7 during chronic virus infections. In this study, we demonstrate that IRF-7 attenuates chronic infection by restricting establishment of gammaherpesvirus latency in the peritoneal cavity and, to a lesser extent, viral reactivation in the spleen. Despite the classical role of IRF-7 as a stimulator of type I interferon (IFN) transcription, there were no global effects on the expression of IFN-induced genes (ISGs) in the absence of IRF-7, with only a few ISGs showing attenuated expression in IRF-7-deficient peritoneal cells. Further, IRF-7 expression was dispensable for the induction of a virus-specific CD8 T cell response. In contrast, IRF-7 expression restricted latent gammaherpesvirus infection in the peritoneal cavity under conditions where the viral latent reservoir is predominantly hosted by peritoneal B cells. This report is the first demonstration of the antiviral role of IRF-7 during the chronic stage of gammaherpesvirus infection.IMPORTANCE The innate immune system of the host is critical for the restriction of acute viral infections. In contrast, the role of the innate immune network during chronic herpesvirus infection remains poorly defined. Interferon regulatory factor 7 (IRF-7) is a transcription factor with many target genes, including type I interferons (IFNs). In this study, we show that the antiviral role of IRF-7 continues into the chronic phase of gammaherpesvirus infection, wherein IRF-7 restricts the establishment of viral latency and viral reactivation. This study is, to our knowledge, the first to define the role of IRF-7 in chronic virus infection.

Molecular characterization of yellow catfish (Pelteobagrus fulvidraco) IRF7 suggests involvement in innate immune response.

Interferon regulatory factor 7 (IRF7) serves as a critical mediator in the regulation of type Ι interferon (IFN) response to invading pathogens. Here, an ortholog of IRF7 was characterized in yellow catfish (Pelteobagrus fulvidraco). The full-length cDNA of PfIRF7 consisted of 1516 bp encoding a polypeptide of 425 amino acids. PfIRF7 protein comprised a typical IRF structural architecture, including a DNA binding domain (DBD), an IRF association domain (IAD) and a serine-rich domain (SRD). PfIRF7 was expressed predominantly in the immune-related tissues and transcriptionally upregulated by PolyI:C, LPS, and Edwardsiella ictaluri. Ectopic expression of PfIRF7 led to activation of fish type I IFN promoters and induction of IFN and Vig1, thereby conferring a strong antiviral effect against spring viremia of carp virus (SVCV). Overall, the present data suggest that PfIRF7 may play an essential role in type I IFN response of yellow catfish.

Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Suppresses Type I Interferon Signaling To Promote EBV Reactivation.

Interferon alpha (IFN-α) and IFN-ß are type I IFNs that are induced by virus infection and are important in the host's innate antiviral response. EBV infection activates multiple cell signaling pathways, resulting in the production of type I IFN which inhibits EBV infection and virus-induced B-cell transformation. We reported previously that EBV tegument protein BGLF2 activates p38 and enhances EBV reactivation. To further understand the role of BGLF2 in EBV infection, we used mass spectrometry to identify cellular proteins that interact with BGLF2. We found that BGLF2 binds to Tyk2 and confirmed this interaction by coimmunoprecipitation. BGLF2 blocked type I IFN-induced Tyk2, STAT1, and STAT3 phosphorylation and the expression of IFN-stimulated genes (ISGs) IRF1, IRF7, and MxA. In contrast, BGLF2 did not inhibit STAT1 phosphorylation induced by IFN-γ. Deletion of the carboxyl-terminal 66 amino acids of BGLF2 reduced the ability of the protein to repress type I IFN signaling. Treatment of gastric carcinoma and Raji cells with IFN-α blocked BZLF1 expression and EBV reactivation; however, expression of BGLF2 reduced the ability of IFN-α to inhibit BZLF1 expression and enhanced EBV reactivation. In summary, EBV BGLF2 interacts with Tyk2, inhibiting Tyk2, STAT1, and STAT3 phosphorylation and impairs type I IFN signaling; BGLF2 also counteracts the ability of IFN-α to suppress EBV reactivation.IMPORTANCE Type I interferons are important for controlling virus infection. We have found that the Epstein-Barr virus (EBV) BGLF2 tegument protein binds to a protein in the type I interferon signaling pathway Tyk2 and inhibits the expression of genes induced by type I interferons. Treatment of EBV-infected cells with type I interferon inhibits reactivation of the virus, while expression of EBV BGLF2 reduces the ability of type I interferon to inhibit virus reactivation. Thus, a tegument protein delivered to cells during virus infection inhibits the host's antiviral response and promotes virus reactivation of latently infected cells. Therefore, EBV BGLF2 might protect virus-infected cells from the type I interferon response in cells undergoing lytic virus replication.