Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion.
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ABSTRACT:
SUBMITTER: Li MM
PROVIDER: S-EPMC5154937 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, Ifit1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or Ifit1. We observed that in Ifit2 knockout (Ifit2(-/-)) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and Ifit1(-/-) mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2(-/-) mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2(-/-) mice and induced interferon-?. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2(-/-) mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2(-/-) mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2(-/-) mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2(-/-) mice. Our study provides a clear demonstration of tissue-, virus- and ISG-specific antiviral action of interferon.
| S-EPMC3355090 | biostudies-literature
Project description:Hendra virus (HeV) and Nipah virus (NiV) are closely related, recently emerged paramyxoviruses that form Henipavirus genus and are capable of causing considerable morbidity and mortality in a number of mammalian species, including humans. However, in contrast to many other species and despite expression of functional virus entry receptors, mice are resistant to henipavirus infection. We report here the susceptibility of mice deleted for the type I interferon receptor (IFNAR-KO) to both HeV and NiV. Intraperitoneally infected mice developed fatal encephalitis, with pathology and immunohistochemical features similar to what was found in humans. Viral RNA was found in the majority of analyzed organs, and sublethally infected animals developed virus-specific neutralizing antibodies. Altogether, these results reveal IFNAR-KO mice as a new small animal model to study HeV and NiV pathogenesis, prophylaxis, and treatment and suggest the critical role of type I interferon signaling in the control of henipavirus infection.
| S-EPMC7107294 | biostudies-literature
Project description:Deciphering the molecular and cellular processes involved in foam cell formation is critical to understanding the pathogenesis of atherosclerosis. Interferon regulatory factor 1 (IRF1) was first identified as a transcriptional regulator of type-I interferons (IFNs) and IFN inducible genes. Our study aims to explore the role of IRF1 in atherosclerotic foam cell formation and understand the functional diversity of IRF1 in various cell types contributing to atherosclerosis. Methods: We induced experimental atherosclerosis in ApoE-/-IRF1-/- mice and evaluated the effect of IRF1 on disease progression and foam cell formation. Results: IRF1 expression was increased in human and mouse atherosclerotic lesions. IRF1 deficiency inhibited modified lipoprotein uptake and promoted cholesterol efflux, along with altered expression of genes implicated in lipid metabolism. Gene expression analysis identified scavenger receptor (SR)-AI as a regulated target of IRF1, and SR-AI silencing completely abrogated the increased uptake of modified lipoprotein induced by IRF1. Our data also explain a mechanism underlying endotoxemia-complicated atherogenesis as follows: two likely pro-inflammatory agents, oxidized low-density lipoprotein (ox-LDL) and bacterial lipopolysaccharide (LPS), exert cooperative effects on foam cell formation, which is partly attributable to a shift of IRF1-Ubc9 complex to IRF1- myeloid differentiation primary response protein 88 (Myd88) complex and subsequent IRF1 nuclear translocation. Additionally, it seems that improved function of vascular smooth muscle cells (VSMCs) also accounts for the diminished and more stable atherosclerotic plaques observed in ApoE-/-IRF1-/- mice. Conclusions: Our findings demonstrate an unanticipated role of IRF1 in the regulation of gene expression implicated in foam cell formation and identify IRF1 activation as a new risk factor in the development, progression and instability of atherosclerotic lesions.
| S-EPMC6643443 | biostudies-literature
Project description:Obesity is a calorie-excessive state associated with high risk of diabetes, atherosclerosis, and certain types of tumors. Obesity may induce inflammation and insulin resistance (IR). We found that the expression of interferon (IFN) regulatory factor 9 (IRF9), a major transcription factor mediating IFN responses, was lower in livers of obese mice than in those of their lean counterparts. Furthermore, whole-body IRF9 knockout (KO) mice were more obese and had aggravated IR, hepatic steatosis, and inflammation after chronic high-fat diet feeding. In contrast, adenoviral-mediated hepatic IRF9 overexpression in both diet-induced and genetically (ob/ob) obese mice showed markedly improved hepatic insulin sensitivity and attenuated hepatic steatosis and inflammation. We further employed a yeast two-hybrid screening system to investigate the interactions between IRF9 and its cofactors. Importantly, we identified that IRF9 interacts with peroxisome proliferator-activated receptor alpha (PPAR-?), an important metabolism-associated nuclear receptor, to activate PPAR-? target genes. In addition, liver-specific PPAR-? overexpression rescued insulin sensitivity and ameliorated hepatic steatosis and inflammation in IRF9 KO mice.IRF9 attenuates hepatic IR, steatosis, and inflammation through interaction with PPAR-?.
| S-EPMC3736732 | biostudies-other
Project description:Interferon regulatory factor 3 (IRF3) has both transcriptional and nontranscriptional functions. Transcriptional activity is dependent on serine phosphorylation of IRF3, while transcription-independent IRF3-mediated apoptosis requires ubiquitination. IRF3 also binds to inhibitor of nuclear factor kappa B kinase (IKKβ) in the cytosol, restricting nuclear translocation of p65. IRF3-deficient mice are highly sensitive to high-fat diet (HFD)-induced liver injury; however, it is not known if transcriptional and/or nontranscriptional activity of IRF3 confers protection. Using a mouse model only expressing nontranscriptional functions of IRF3 (Irf3 S1/S1), we tested the hypothesis that nontranscriptional activity of IRF3 protects mice from HFD-induced liver injury. C57BL/6, Irf3 -/-, and Irf3 S1/S1 mice were fed an HFD for 12 weeks. In C57BL/6 mice, the HFD increased expression of interferon (IFN)-dependent genes, despite a decrease in IRF3 protein in the liver. The HFD had no impact on IFN-dependent gene expression Irf3 -/- or Irf3 S1/S1 mice, both lacking IRF3 transcriptional activity. Liver injury, apoptosis, and fibrosis were exacerbated in Irf3 -/- compared to C57BL/6 mice following the HFD; this increase was ameliorated in Irf3 S1/S1 mice. Similarly, expression of inflammatory cytokines as well as numbers of neutrophils and infiltrating monocytes was increased in Irf3 -/- mice compared to C57BL/6 and Irf3 S1/S1 mice. While the HFD increased the ubiquitination of IRF3, a response associated with IRF3-mediated apoptosis, in Irf3 S1/S1 mice, protection from liver injury was not due to differences in apoptosis of hepatocytes or immune cells. Instead, protection from HFD-induced liver injury in Irf3 S1/S1 mice was primarily associated with retardation of nuclear translocation of p65 and decreased expression of nuclear factor kappa B (NFκB)-dependent inflammatory cytokines. Conclusion: Taken together, these data identify important contributions of the nontranscriptional function of IRF3, likely by reducing NFκB signaling, in dampening the hepatic inflammatory environment in response to an HFD.
| S-EPMC6887899 | biostudies-literature
Project description:Viral replication efficiency is in large part governed by the ability of viruses to counteract pro-apoptotic signals induced by infection of the host cell. Human herpesvirus 8 (HHV-8) uses several strategies to block the host's innate antiviral defenses via interference with interferon and apoptotic signaling. Contributors include the four viral interferon regulatory factors (vIRFs 1-4), which function in dominant negative fashion to block cellular IRF activities in addition to targeting IRF signaling-induced proteins such as p53 and inhibiting other inducers of apoptosis such as TGFbeta receptor-activated Smad transcription factors. Here we identify direct targeting by vIRF-1 of BH3-only pro-apoptotic Bcl-2 family member Bim, a key negative regulator of HHV-8 replication, to effect its inactivation via nuclear translocation. vIRF-1-mediated relocalization of Bim was identified in transfected cells, by both immunofluorescence assay and western analysis of fractionated cell extracts. Also, co-localization of vIRF-1 and Bim was detected in nuclei of lytically infected endothelial cells. In vitro co-precipitation assays using purified vIRF-1 and Bim revealed direct interaction between the proteins, and Bim-binding residues of vIRF-1 were mapped by deletion and point mutagenesis. Generation and experimental utilization of Bim-refractory vIRF-1 variants revealed the importance of vIRF-1:Bim interaction, specifically, in pro-replication and anti-apoptotic activity of vIRF-1. Furthermore, blocking of the interaction with cell-permeable peptide corresponding to the Bim-binding region of vIRF-1 confirmed the relevance of vIRF-1:Bim association to vIRF-1 pro-replication activity. To our knowledge, this is the first report of an IRF protein that interacts with a Bcl-2 family member and of nuclear sequestration of Bim or any other member of the family as a means of inactivation. The data presented reveal a novel mechanism utilized by a virus to control replication-induced apoptosis and suggest that inhibitory targeting of vIRF-1:Bim interaction may provide an effective antiviral strategy.
| S-EPMC2916877 | biostudies-other
Project description:Enterovirus 71 (EV71) causes hand-foot-and-mouth diseases as well as neurological complications in young children. Interferon (IFN) can inhibit the replication of many viruses with low cytotoxic effects. Previously, an adenovirus vectored mouse interferon-? (DEF201), subtype 5, was generated by Wu et al, 2007. In this study, the antiviral effects of DEF201 against EV71 were evaluated in a murine model. 6-day-old BALB/c mice were administered a single dose of DEF201 before or after infection with lethal dose of EV71. The survival rate, clinical symptoms, tissue viral loads and histology pathogenesis were evaluated. IFN gene expression following a single dose of DEF201 maintained high concentrations of 100-9000 pg/mL for more than 7 days in mice serum. Pre-infection administration of a single dose of 106 PFU of DEF201 offered full protection of the mice against EV71 infection compared with the empty Ad5 vector control. In addition, virus load in DEF201-treated mice muscle tissue was significantly decreased as compared with empty vector control. Histopathology analysis revealed that DEF201 significantly prevented the development of severe tissue damage with reduction of viral antigen in the murine muscle tissue. Post-infection treatment at 6 h offered full protection and partial protection at 12 h, indicating that DEF201 could be used as an anti-EV71 therapeutic agent in early stage of EV71 infection. In addition, our study showed that DEF201 enhanced the neutralization ability of serum in EV71-vaccinated mice, implying that DEF201 could promote the production of specific anti-EV71 antibodies. In conclusion, single dose of DEF201 is highly efficacious as a prophylactic agent against EV71 infection in vivo.
| S-EPMC7113890 | biostudies-literature
Project description:The innate immune system protects cells against invading viral pathogens by the auto- and paracrine action of type I interferon (IFN). In addition, the interferon regulatory factor (IRF)-1 can induce alternative intrinsic antiviral responses. Although both, type I IFN and IRF-1 mediate their antiviral action by inducing overlapping subsets of IFN stimulated genes, the functional role of this alternative antiviral action of IRF-1 in context of viral infections in vivo remains unknown. Here, we report that IRF-1 is essential to counteract the neuropathology of vesicular stomatitis virus (VSV). IFN- and IRF-1-dependent antiviral responses act sequentially to create a layered antiviral protection program against VSV infections. Upon intranasal infection, VSV is cleared in the presence or absence of IRF-1 in peripheral organs, but IRF-1-/- mice continue to propagate the virus in the brain and succumb. Although rapid IFN induction leads to a decline in VSV titers early on, viral replication is re-enforced in the brains of IRF-1-/- mice. While IFN provides short-term protection, IRF-1 is induced with delayed kinetics and controls viral replication at later stages of infection. IRF-1 has no influence on viral entry but inhibits viral replication in neurons and viral spread through the CNS, which leads to fatal inflammatory responses in the CNS. These data support a temporal, non-redundant antiviral function of type I IFN and IRF-1, the latter playing a crucial role in late time points of VSV infection in the brain.
| S-EPMC3968136 | biostudies-other
Project description:Interferon (IFN) genes are among the earliest transcriptional responses to virus infection of mammalian cells. Although the regulation of the IFNbeta gene has been well characterized, the induction of the large family of IFNalpha genes has remained obscure. We report that the IFNalpha genes can be divided into two groups: an immediate-early response gene (IFNalpha4) which is induced rapidly and without the need for ongoing protein synthesis; and a set of genes that display delayed induction, consisting of at least IFNalpha2, 5, 6 and 8, which are induced more slowly and require cellular protein synthesis. One protein that must be synthesized for induction of the delayed gene set is IFN itself, presumably IFNalpha4 or IFNbeta, which stimulates the Jak-Stat pathway through the IFN receptor, resulting in activation of the transcription factor interferon-stimulated gene factor 3 (ISGF3). Among the IFN-stimulated genes induced through this positive feedback loop is the IFN regulatory factor (IRF) protein, IRF7. Induction of IRF7 protein in response to IFN and its subsequent activation by phosphorylation in response to virus-specific signals, involving two C-terminal serine residues, are required for induction of the delayed IFNalpha gene set.
| S-EPMC1171011 | biostudies-other
Project description:BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with unknown etiology. Interferon-? (IFN-?), a member of the type I IFN family, is used as a therapeutic for MS and the IFN signaling pathway is implicated in MS susceptibility. Interferon regulatory factor 7 (IRF7) is critical for the induction and positive feedback regulation of type I IFN. To establish whether and how endogenous type I IFN signaling contributes to disease modulation and to better understand the underlying mechanism, we examined the role of IRF7 in the development of MS-like disease in mice. METHODS: The role of IRF7 in development of EAE was studied by immunizing IRF7-KO and C57BL/6 (WT) mice with myelin oligodendrocyte glycoprotein using a standard protocol for the induction of EAE. We measured leukocyte infiltration and localization in the CNS using flow cytometric analysis and immunohistochemical procedures. We determined levels of CD3 and selected chemokine and cytokine gene expression by quantitative real-time PCR. RESULTS: IRF7 gene expression increased in the CNS as disease progressed. IRF7 message was localized to microglia and infiltrating leukocytes. Furthermore, IRF7-deficient mice developed more severe disease. Flow cytometric analysis showed that the extent of leukocyte infiltration into the CNS was higher in IRF7-deficient mice with significantly higher number of infiltrating macrophages and T cells, and the distribution of infiltrates within the spinal cord was altered. Analysis of cytokine and chemokine gene expression by quantitative real-time PCR showed significantly greater increases in CCL2, CXCL10, IL-1? and IL17 gene expression in IRF7-deficient mice compared with WT mice. CONCLUSION: Together, our findings suggest that IRF7 signaling is critical for regulation of inflammatory responses in the CNS.
| S-EPMC3260126 | biostudies-literature