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

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.

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

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.

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

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.

Role of interferon regulatory factor 7 in corneal endothelial cells after HSV-1 infection

Viral infections of the cornea including herpes simplex virus 1 (HSV-1) cause visual morbidity, and the corneal endothelial cell damage leads to significant visual impairment. Interferon regulatory factor 7 (IRF7) has been identified as a significant regulator in corneal endothelial cells after an HSV-1 infection. To examine the role played by IRF7, the DNA binding domain (DBD) of IRF7 of human corneal endothelial cells (HCEn) was disrupted. An RNAi inhibition of IRF7 and IRF7 DBD disruption (IRF7 ∆DBD) led to an impairment of IFN-β production. Impaired IFN-β production by IRF7 ∆DBD was regained by IRF7 DNA transfection. Transcriptional network analysis indicated that IRF7 plays a role in antigen presentation function of corneal endothelial cells. When the antigen presentation activity of HCEn cells were examined for priming of memory CD8 T cells, IRF7 disruption abolished the anti-viral cytotoxic T lymphocyte (CTL) response which was dependent on the major histocompatibility complex (MHC) class I. To further examine the roles played by IRF7 in CTL induction as acquired immunity, the contribution of IRF7 to MHC class I-mediated antigen presentation was assessed. Analysis of IRF7 ∆DBD cells indicated that IRF7 played an unrecognized role in MHC class I induction, and the viral infection induced-MHC class I induction was abolished by IRF7 disruption. Collectively, the IRF7 in corneal endothelial cells not only contributed to type I IFN response, but also to the mediation of viral infection-induced MHC class I upregulation and priming of CD8 arm of acquired immunity.

Role of Interferon Regulatory Factor 7 in Corneal Endothelial Cells After HSV-1 Infection

Viral infections of the cornea including herpes simplex virus 1 (HSV-1) cause visual morbidity, and the corneal endothelial cell damage leads to significant visual impairment. Interferon regulatory factor 7 (IRF7) has been identified as a significant regulator in corneal endothelial cells after an HSV-1 infection. To examine the role played by IRF7, the DNA binding domain (DBD) of IRF7 of human corneal endothelial cells (HCEn) was disrupted. An RNAi inhibition of IRF7 and IRF7 DBD disruption (IRF7 ∆DBD) led to impairment of IFN-β production. Impaired IFN-β production by IRF7 ∆DBD was regained by IRF7 DNA transfection. Transcriptional network analysis indicated that IRF7 played a role in antigen presentation function of corneal endothelial cells. When the antigen presentation activity of HCEn cells were examined for priming of memory CD8 T cells, IRF7 disruption abolished the anti-viral CTL response, which was dependent on major histocompatibility complex (MHC) class I.To further examine roles of IRF7 in CTL induction as acquired immunity, contribution of IRF7 to MHC class I-mediated antigen presentation was assessed. Analysis of IRF7 ∆DBD cells indicated that IRF7 has previously unrecognized role in MHC class I induction, and viral infection induced-MHC class I induction was abolished by IRF7 disruption.Collectively, the IRF7 in corneal endothelial cells not only contributes to type I IFN response, but also mediates viral infection-induced MHC class I upregulation and priming of CD8 arm of acquired immunity.

Differential Expression of Cow Innate and Adaptive Responses Genes in Response to Eugenol

Dietary phytochemicals have both nutritional and health benefits for farm animals. Research on the immunomodulatory effects of phytochemicals may aid in developing novel therapeutic agents and provide insights into the regulation of gene expression. Eugenol (4-allyl-2-methoxyphenyl) is the active ingredient in clove oil that has been studied for its immunomodulatory/anti-inflammatory effects. The objective of this study was to evaluate the effect of eugenol on the expression of genes associated with the cow’s innate and adaptive immune responses. Blood was collected from (n = 3) clinically healthy Holstein-Friesian cows from the North Carolina A&T State University Dairy Unit. One milliliter of whole blood from three cows was treated individually with 10 ng/mL of Eugenol (Sigma-Aldrich St. Louis, MO), or maintained in PBS, incubated at 37ºC for 30 minutes. Total RNA was extracted, reverse transcribed, and real-time PCR was carried out using the RT2 Profiler™ human Innate & Adaptive Immune Responses PCR Array containing 84 genes, as recommended by the manufacturer (Qiagen). The Livak method was used to calculate fold change (FC >2 considered significant). The analysis showed that 25 genes out of 84 genes were affected by treatment with eugenol. Among 25 genes, 19 were upregulated, and 2 genes were downregulated. The highest up-regulated and down-regulated genes following exposure to eugenol was IL23A and Interferon Regulatory Factor 7 (IRF7), respectively. The upregulation of the IL-23A gene expression by exogenous eugenol may be important in the production of pro-inflammatory cytokines and warrants further studies to investigate the mechanism involved. Interferon Regulatory Factor 7 is a critical regulator of type I interferon production and plays an important role in innate immune responses. The observed transcriptional expression of IL23A and IRF7 by eugenol provides an insight into immune modulation in cow blood.

Interferon Regulatory Factor 7 impairs cellular metabolism with age in adipose-derived stromal cells

Dysregulated immunity and widespread metabolic dysfunctions are the most relevant hallmarks of the passing time over the adult life and their combination at midlife is strongly related to increased vulnerability to diseases. However, their causal connection remains largely unclear. Combining multi-omics and functional analyses on adipose derived stromal cells established from young (1 month) and midlife (12 months) mice we show that the increase of Interferon Regulatory Factor 7 (IRF7) over the adult life drives major metabolic changes, which includes impaired mitochondrial function, altered amino acid biogenesis and reduced expression of genes involved in branched chain amino acid (BCAA) degradation. Our results draw a new paradigm of aging as the 'sterile' activation of a cell-autonomous pathway of self-defense and identify a crucial mediator of this pathway, IRF7, as driver of metabolic dysfunction with age.