Type III Interferons: Emerging Roles in Autoimmunity.

Type III interferons (IFNs) or the lambda IFNs (IFNLs or IFN-λs) are antimicrobial cytokines that play key roles in immune host defense at endothelial and epithelial barriers. IFNLs signal via their heterodimeric receptor, comprised of two subunits, IFNLR1 and interleukin (IL)10Rß, which defines the cellular specificity of the responses to the cytokines. Recent studies show that IFNL signaling regulates CD4+ T cell differentiation, favoring Th1 cells, which has led to the identification of IFNL as a putative therapeutic target for autoimmune diseases. Here, we summarize the IFNL signaling pathways during antimicrobial immunity, IFNL-mediated immunomodulation of both innate and adaptive immune cells, and induction of autoimmunity.

Optimal ligand discrimination by asymmetric dimerization and turnover of interferon receptors.

In multicellular organisms, antiviral defense mechanisms evoke a reliable collective immune response despite the noisy nature of biochemical communication between tissue cells. A molecular hub of this response, the interferon I receptor (IFNAR), discriminates between ligand types by their affinity regardless of concentration. To understand how ligand type can be decoded robustly by a single receptor, we frame ligand discrimination as an information-theoretic problem and systematically compare the major classes of receptor architectures: allosteric, homodimerizing, and heterodimerizing. We demonstrate that asymmetric heterodimers achieve the best discrimination power over the entire physiological range of local ligand concentrations. This design enables sensing of ligand presence and type, and it buffers against moderate concentration fluctuations. In addition, receptor turnover, which drives the receptor system out of thermodynamic equilibrium, allows alignment of activation points for ligands of different affinities and thereby makes ligand discrimination practically independent of concentration. IFNAR exhibits this optimal architecture, and our findings thus suggest that this specialized receptor can robustly decode digital messages carried by its different ligands.

A Mouse Model of PPRV Infection for Elucidating Protective and Pathological Roles of Immune Cells.

The study was aimed at developing an accessible laboratory animal model to elucidate protective and pathological roles of immune mediators during Peste des petits ruminants virus (PPRV) infection. It is because of the critical roles of type I IFNs in anti-viral defense, we assessed the susceptibility of IFN receptor knock out (IFNR KO) mice to PPRV infection. IFNR KO mice were exceedingly susceptible to the infection but WT animals efficiently controlled PPRV. Accordingly, the PPRV infected IFNR KO mice gradually reduced their body weights and succumbed to the infection within 10 days irrespective of the dose and route of infection. The lower infecting doses predominantly induced immunopathological lesions. The viral antigens as well as the replicating PPRV were abundantly present in most of the critical organs such as brain, lungs, heart and kidneys of IFNR KO mice infected with high dose of the virus. Neutrophils and macrophages transported the replicating virus to central nervous system (CNS) and contributed to pathology while the elevated NK and T cell responses directly correlated with the resolution of PPRV infection in WT animals. Using an array of fluorescently labeled H-2Kb tetramers, we discovered four immunogenic epitopes of PPRV. The PPRV-peptides interacted well with H-2Kb in acellular and cellular assay as well as expanded the virus-specific CD8+ T cells in immunized or infected mice. Adoptively transferred CD8+ T cells helped control PPRV in infected mice. Our study therefore established and employed a mouse model for investigating the pathogenesis of PPRV. The model could be useful for elucidating the contribution of immune cells in disease progression as well as to test anti-viral agents.

Rapid Depletion of Intratumoral Regulatory T Cells Induces Synchronized CD8 T- and NK-cell Activation and IFNγ-Dependent Tumor Vessel Regression.

Regulatory T cells (Tregs) are known to inhibit antitumor immunity, yet the specific mechanism by which intratumoral Tregs promote tumor growth remains unclear. To better understand the roles of intratumoral Tregs, we selectively depleted tumor-infiltrating Tregs using anti-CD25-F(ab')2 near-infrared photoimmunotherapy. Depletion of tumor-infiltrating Tregs induced transient but synchronized IFNγ expression in CD8 T and natural killer (NK) cells. Despite the small fraction of CD8 T and NK cells contained within examined tumors, IFNγ produced by these CD8 T and NK cells led to efficient and rapid tumor vessel regression, intratumoral ischemia, and tumor necrosis/apoptosis and growth suppression. IFNγ receptor expression on vascular endothelial cells was required for these effects. Similar findings were observed in the early phase of systemic Treg depletion in tumor-bearing Foxp3DTR mice; combination with IL15 therapy further inhibited tumor growth and achieved increased complete regression. These results indicate the pivotal roles of intratumoral Tregs in maintaining tumor vessels and tumor growth by suppressing CD8 T and NK cells from producing IFNγ, providing insight into the mechanism of Treg-targeting therapies. SIGNIFICANCE: Intratumoral Treg depletion induces synchronized intratumoral CD8 T- and NK-cell activation, IFNγ-dependent tumor vessel regression, and ischemic tumor necrosis/apoptosis, indicating the roles of intratumoral Tregs to support the tumor vasculature. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/3092/F1.large.jpg.

Silencing IFNγ inhibits A1 astrocytes and attenuates neurogenesis decline and cognitive impairment in endotoxemia.

Cognitive impairment, acute or long-term, is a common complication in patients with severe bacterial infection. However, the underlying mechanisms are not fully verified and effective medicine is not available in clinics. Interferon gamma (IFNγ) is a pivotal cytokine against infection and is believed to be a tune in homeostasis of cognitive function. Here, we collected blood and cerebrospinal fluid (CF) from human subjects and mice, and found that plasma and CF levels of IFNγ were significantly increased in septic patients and endotoxin-challenged mice when compared with healthy controls. IFNγ signaling was boosted in the hippocampus of mice after a challenge of lipopolysaccharide (LPS), which was accompanied with cognitive impairment and decline of neurogenesis. Deficiency of IFNγ or its receptor (IFNγR) dramatically attenuated microglia-induced A1 astrocytes and consequently restored neurogenesis and cognitive function in endotoxemia mice model. Using primary microglia, astrocytes and neurons, we found that IFNγ remarkably increased LPS-mediated release of TNFα and IL-1α in microglia and consequently induced the transformation of astrocyte to A1 subtype, which ultimately resulted in neuron damage. Thus, IFNγ promotes cognitive impairment in endotoxemia by enhancing microglia-induced A1 astrocytes. Targeting IFNγ would be a novel strategy for preventing or treating cognitive dysfunction in patients with Gram-negative infection.

Ex vivo conditioning with IL-12 protects tumor-infiltrating CD8+ T cells from negative regulation by local IFN-γ.

Optimal ex vivo expansion protocols for adoptive cell therapy (ACT) must yield T cells able to effectively home to tumors and survive the inhospitable conditions of the tumor microenvironment (TME), while simultaneously exerting persistent anti-tumor effector functions. Our previous work has shown that ex vivo activation in the presence of IL-12 can induce optimal expansion of murine CD8+ T cells, thus resulting in significant tumor regression after ACT mostly via sustained secretion of IFN-γ. In this report, we further elucidate the mechanism of this potency, showing that IL-12 additionally counteracts the negative regulatory effects of autocrine IFN-γ. IL-12 not only downregulates PD-1 expression by T cells, thus minimizing the effects of IFN-γ-induced PD-L1 upregulation by tumor stromal cells, but also inhibits IFNγR2 expression, thereby protecting T cells from IFN-γ-induced cell death. Thus, the enhanced anti-tumor activity of CD8+ T cells expanded ex vivo in the presence of IL-12 is due not only to the ability of IL-12-stimulated cells to secrete sustained levels of IFN-γ, but also to the additional capacity of IL-12 to counter the negative regulatory effects of autocrine IFN-γ.

IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission.

Host factors restricting the transmission of respiratory viruses are poorly characterized. We analyzed the contribution of type I and type III interferon (IFN) using a mouse model in which the virus is selectively administered to the upper airways, mimicking a natural respiratory virus infection. Mice lacking functional IFN-λ receptors (Ifnlr1-/-) no longer restricted virus dissemination from the upper airways to the lungs. Ifnlr1-/- mice shed significantly more infectious virus particles via the nostrils and transmitted the virus much more efficiently to naïve contacts compared with wild-type mice or mice lacking functional type I IFN receptors. Prophylactic treatment with IFN-α or IFN-λ inhibited initial virus replication in all parts of the respiratory tract, but only IFN-λ conferred long-lasting antiviral protection in the upper airways and blocked virus transmission. Thus, IFN-λ has a decisive and non-redundant function in the upper airways that greatly limits transmission of respiratory viruses to naïve contacts.

Accelerated tumour metastasis due to interferon-γ receptor-mediated dissociation of perivascular cells from blood vessels.

Angiostasis mediated by interferon (IFN)-γ is a key mechanism of anti-tumour immunity; however, the effect of IFN-γ on host vascular endothelial growth factor A (VEGFA)-expressing cells during tumour progression is still elusive. Here, we developed transgenic mice with IFN-γ receptor (IFNγR) expression under control of the Vegfa promoter (V-γR). In these mice, the IFN-γ responsiveness of VEGFA-expressing cells led to dramatic growth suppression of transplanted lung carcinoma cells. Surprisingly, increased mortality and tumour metastasis were observed in the tumour-bearing V-γR mice, in comparison with the control wild-type and IFNγR-deficient mice. Further study showed that perivascular cells were VEGFA-expressing cells and potential IFN-γ targets. In vivo, tumour vascular perfusion and pericyte association with blood vessels were massively disrupted in V-γR mice. In vitro, IFN-γ inhibited transforming growth factor-ß signalling by upregulating SMAD7, and therefore downregulated N-cadherin expression in pericytes. Importantly, IFN-γ neutralization in vivo with a monoclonal antibody reduced tumour metastasis. Together, the results suggest that IFNγR-mediated dissociation of perivascular cells from blood vessels contributes to the acceleration of tumour metastasis. Thus, the inhibition of tumour growth via IFN-γ-induced angiostasis might also accelerate tumour metastasis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Efficient analysis of mouse genome sequences reveal many nonsense variants.

Genetic polymorphisms in coding genes play an important role when using mouse inbred strains as research models. They have been shown to influence research results, explain phenotypical differences between inbred strains, and increase the amount of interesting gene variants present in the many available inbred lines. SPRET/Ei is an inbred strain derived from Mus spretus that has ∼1% sequence difference with the C57BL/6J reference genome. We obtained a listing of all SNPs and insertions/deletions (indels) present in SPRET/Ei from the Mouse Genomes Project (Wellcome Trust Sanger Institute) and processed these data to obtain an overview of all transcripts having nonsynonymous coding sequence variants. We identified 8,883 unique variants affecting 10,096 different transcripts from 6,328 protein-coding genes, which is about 28% of all coding genes. Because only a subset of these variants results in drastic changes in proteins, we focused on variations that are nonsense mutations that ultimately resulted in a gain of a stop codon. These genes were identified by in silico changing the C57BL/6J coding sequences to the SPRET/Ei sequences, converting them to amino acid (AA) sequences, and comparing the AA sequences. All variants and transcripts affected were also stored in a database, which can be browsed using a SPRET/Ei M. spretus variants web tool (www.spretus.org), including a manual. We validated the tool by demonstrating the loss of function of three proteins predicted to be severely truncated, namely Fas, IRAK2, and IFNγR1.

The Emerging Duck Flavivirus Is Not Pathogenic for Primates and Is Highly Sensitive to Mammalian Interferon Antiviral Signaling.

UNLABELLED: Flaviviruses pose a significant threat to both animals and humans. Recently, a novel flavivirus, duck Tembusu virus (DTMUV), was identified to be the causative agent of a serious duck viral disease in Asia. Its rapid spread, expanding host range, and uncertain transmission routes have raised substantial concerns regarding its potential threats to nonavian hosts, including humans. Here, we demonstrate that DTMUV is not pathogenic for nonhuman primates and is highly sensitive to mammal type I interferon (IFN) signaling. In vitro assays demonstrated that DTMUV infected and replicated efficiently in various mammalian cell lines. Further tests in mice demonstrated high neurovirulence and the age-dependent neuroinvasiveness of the virus. In particular, the inoculation of DTMUV into rhesus monkeys did not result in either viremia or apparent clinical symptoms, although DTMUV-specific humoral immune responses were detected. Furthermore, we revealed that although avian IFN failed to inhibit DTMUV in avian cells, DTMUV was more sensitive to the antiviral effects of type I interferon than other known human-pathogenic flaviviruses. Knockout of the type I IFN receptor in mice caused apparent viremia, viscerotropic disease, and mortality, indicating a vital role of IFN signaling in protection against DTMUV infection. Collectively, we provide direct experimental evidence that this novel avian-origin DTMUV possesses a limited capability to establish infection in immunocompetent primates due to its decreased antagonistic activity in the mammal IFN system. Furthermore, our findings highlight the potential risk of DTMUV infection in immunocompromised individuals and warrant studies on the cross-species transmission and pathogenesis of this novel flavivirus. IMPORTANCE: Mosquito-borne flaviviruses comprise a large group of pathogenic and nonpathogenic members. The pathogenic flaviviruses include dengue, West Nile, and Japanese encephalitis viruses, and the nonpathogenic flaviviruses normally persist in a natural cycle and rarely cause disease in humans. A novel flavivirus, DTMUV (also known as duck egg drop syndrome flavivirus [DEDSV]) was identified in 2012 in ducks and then rapidly spread to several Asian countries. This new flavivirus was then shown to infect multiple avian species, resulting in neurological symptoms with unknown routes of transmission. There is public concern regarding its potential transmission from birds to humans and other nonavian hosts. Our present study shows that the mammalian IFN system can efficiently eliminate DTMUV infection and that the emergence of severe DTMUV-associated disease in mammals, especially humans, is unlikely. Currently, DTMUV infection mostly affects avian species.

IFN-γ-mediated hematopoietic cell destruction in murine models of immune-mediated bone marrow failure.

Interferon gamma (IFN-γ) has been reported to have both negative and positive activity on hematopoietic cells, adding complexity to the interpretation of its pleiotropic functions. We examined the effects of IFN-γ on murine hematopoietic stem cells (HSCs) and progenitors in vitro and in vivo by using mouse models. IFN-γ treatment expanded bone marrow (BM) c-Kit(+)Sca1(+)Lin(-) (KSL) cell number but reduced BM KLCD150(+) and KLCD150(+)CD48(-) cells. IFN-γ-expanded KSL cells engrafted poorly when tested by competitive repopulation in vivo. KSL, KLCD150(+), and KLCD150(+)CD48(-) cells from IFN-γ-treated animals all showed significant upregulation in Fas expression. When cocultured with activated T cells in vitro, KSL and KLCD150(+) cells from IFN-γ-treated donors showed increased apoptosis relative to those from untreated animals, and infusion of activated CD8 T cells into IFN-γ-injected animals in vivo led to partial elimination of KSL cells. Exposure of BM cells or KSL cells to IFN-γ increased expression of Fas, caspases, and related proapoptotic genes and decreased expression of Ets-1 and other hematopoietic genes. In mouse models of BM failure, mice genetically deficient in IFN-γ receptor expression showed attenuation of immune-mediated marrow destruction, whereas effector lymphocytes from IFN-γ-deficient donors were much less potent in initiating BM damage. We conclude that the activity of IFN-γ on murine hematopoiesis is context dependent. IFN-γ-augmented apoptotic gene expression facilitates destruction of HSCs and progenitors in the presence of activated cytotoxic T cells, as occurs in human BM failure.

IFNλ Stimulates MxA Production in Human Dermal Fibroblasts via a MAPK-Dependent STAT1-Independent Mechanism.

IFNλ is important for epidermal defense against viruses. It is produced by, and acts on, keratinocytes, whereas fibroblasts were previously considered to be unresponsive to this type III IFN. Herein we report findings revealing cell type-specific differences in IFNλ signaling and function in skin resident cells. In dermal fibroblasts, IFNλ induced the expression of myxovirus protein A (MxA), a potent antiviral factor, but not other IFN signature genes as it does in primary keratinocytes. In contrast to its effect on keratinocytes, IFNλ did not phosphorylate signal transducer and activator of transcription 1 in fibroblasts, but instead activated mitogen activated protein kinases (MAPK). Accordingly, inhibition of MAPK activation (p38 and p42/44) blocked the expression of MxA protein in fibroblasts but not in keratinocytes. Functionally, IFNλ inhibited proliferation in keratinocytes but not in fibroblasts. Moreover, IFNλ upregulated the expression of Tumor growth factor beta 1 (TGFß1)-induced collagens in fibroblasts. Taken together, our findings identify primary human dermal fibroblasts as responder cells to IFNλ. Our study shows cutaneous cell type-specific IFN signaling and suggests that IFNλ, although important for epidermal antiviral competence, may also have a regulatory role in the dermal compartment balancing type I IFN-induced inhibition of tissue repair processes.

Lifespan of mice and primates correlates with immunoproteasome expression.

There is large variation in lifespan among different species, and there is evidence that modulation of proteasome function may contribute to longevity determination. Comparative biology provides a powerful tool for identifying genes and pathways that control the rate of aging. Here, we evaluated skin-derived fibroblasts and demonstrate that among primate species, longevity correlated with an elevation in proteasomal activity as well as immunoproteasome expression at both the mRNA and protein levels. Immunoproteasome enhancement occurred with a concurrent increase in other elements involved in MHC class I antigen presentation, including ß-2 microglobulin, (TAP1), and TAP2. Fibroblasts from long-lived primates also appeared more responsive to IFN-γ than cells from short-lived primate species, and this increase in IFN-γ responsiveness correlated with elevated expression of the IFN-γ receptor protein IFNGR2. Elevation of immunoproteasome and proteasome activity was also observed in the livers of long-lived Snell dwarf mice and in mice exposed to drugs that have been shown to extend lifespan, including rapamycin, 17-α-estradiol, and nordihydroguaiaretic acid. This work suggests that augmented immunoproteasome function may contribute to lifespan differences in mice and among primate species.

Composition of intestinal microbiota in immune-deficient mice kept in three different housing conditions.

BACKGROUND: Abundance of commensals constituting the intestinal microbiota (IM) affects the immune system and predisposes to a variety of diseases, including intestinal infections, cancer, inflammatory and metabolic disorders. Housing conditions determine the IM and can hence influence the immune system. We analyzed how both variables affect the IM of four immune-compromized mouse lines kept under different housing conditions. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the IM composition in mice by quantitative 16S rRNA RT-PCR analysis of the main fecal bacterial groups (Enterobacteriaceae, enterococci, lactobacilli, bifidobacteria, Bacteroides/Prevotella (BP) spp., Clostridium leptum and coccoides groups). Mice were homozygous (HO) or heterozygous (HE) for a targeted inactivating mutation of either the IFN-γ Receptor (R), IFN-γ, Rag1 or IL-4 genes. Overall, differences in IM composition were subtle. However, in the SPF-barrier, total eubacterial loads were higher in Rag1 HE versus Rag1 HO mice as well as in IFN-γR HE versus IFN-γR HO and WT animals. Although absent in WT mice, bifidobacterial loads were higher in HO and HE IFN-γ and Rag1 as well as IL-4 HO mice. Furthermore, BP was slightly lower in HO and HE IFN-γR and IFN-γ mice as well as in IL-4 HO mice as compared to WT controls. Interestingly, IM compositions were comparable in WT mice when kept in individual ventilated cages (IVC) or open cages (OC). IFN-γ HO and HE mice, however, had higher enterobacteria and BP loads, but lacked bifidobacteria when kept in OC versus IVC, as was the case in HO and HE Rag1 mice. In addition, Rag1 HO mice harbored higher clostridial loads when housed in OC as compared to IVC. Unexpectedly, lactobacilli levels were higher in IFN-γR mice when kept in OC versus IVC. CONCLUSION/SIGNIFICANCE: Housing-dependent and immune-deficiency mediated changes in intestinal microbiota composition were rather subtle but may nevertheless impact immunopathology in experimental models.

Synthetic antibodies with a human framework that protect mice from lethal Sudan ebolavirus challenge.

The ebolaviruses cause severe and rapidly progressing hemorrhagic fever. There are five ebolavirus species; although much is known about Zaire ebolavirus (EBOV) and its neutralization by antibodies, little is known about Sudan ebolavirus (SUDV), which is emerging with increasing frequency. Here we describe monoclonal antibodies containing a human framework that potently inhibit infection by SUDV and protect mice from lethal challenge. The murine antibody 16F6, which binds the SUDV envelope glycoprotein (GP), served as the starting point for design. Sequence and structural alignment revealed similarities between 16F6 and YADS1, a synthetic antibody with a humanized scaffold. A focused phage library was constructed and screened to impart 16F6-like recognition properties onto the YADS1 scaffold. A panel of 17 antibodies were characterized and found to have a range of neutralization potentials against a pseudotype virus infection model. Neutralization correlated with GP binding as determined by ELISA. Two of these clones, E10 and F4, potently inhibited authentic SUDV and conferred protection and memory immunity in mice from lethal SUDV challenge. E10 and F4 were further shown to bind to the same epitope on GP as 16F6 with comparable affinities. These antibodies represent strong immunotherapeutic candidates for treatment of SUDV infection.

IFNγ and perforin cooperate to control infection and prevent fatal pathology during persistent gammaherpesvirus infection in mice.

Infection with murine gammaherpesvirus 68 has become an accepted model for studying the virus/host interactions with regard to gammaherpesvirus infections. Previous studies using gene-deficient mice have revealed that neither IFNγ nor perforin is essential in controlling the outcome of infection or the virus load during chronic infection in C57BL/6 mice. However, pronounced multiorgan fibrosis and splenic atrophy are observed in mice lacking IFNγ or the IFNγ receptor. To study the interplay between perforin and IFNγ in controlling the virus-induced pathology and the viral load during chronic gammaherpesvirus infection, we infected IFNγ/perforin double-deficient C57BL/6 mice and followed the course of infection. While absence of perforin prevented the splenic atrophy in IFNγ-deficient mice, fibrosis did not disappear. Moreover, double-deficient mice developed extreme splenomegaly, were unable to control the viral load and displayed chronic immune activation. Thus, IFNγ and perforin act in concert to minimize pathology and control the viral load in mice chronically infected with MHV68. Furthermore, while certain aspect of the virus-induced pathology in IFNγ-deficient mice may be alleviated in double-deficient mice, other aspects are exaggerated, and the normal architecture of the spleen is completely destroyed. We believe that these findings add to the understanding of the virus/host interaction during chronic gammaherpes virus infection.

MyD88- and TRIF-independent induction of type I interferon drives naive B cell accumulation but not loss of lymph node architecture in Lyme disease.

Rapidly after infection, live Borrelia burgdorferi, the causative agent of Lyme disease, is found within lymph nodes, causing rapid and strong tissue enlargement, a loss of demarcation between B cell follicles and T cell zones, and an unusually large accumulation of B cells. We sought to explore the mechanisms underlying these changes, as lymph tissue disruption could be detrimental for the development of robust Borrelia-specific immunity. A time course study demonstrated that the loss of the normal lymph node structure was a distinct process that preceded the strong increases in B cells at the site. The selective increases in B cell frequencies were due not to proliferation but rather to cytokine-mediated repositioning of B cells to the lymph nodes, as shown with various gene-targeted and bone marrow irradiation chimeras. These studies demonstrated that B. burgdorferi infection induced type I interferon receptor (IFNR) signaling in lymph nodes in a MyD88- and TRIF-independent manner and that type I IFNR indirect signaling was required for the excessive increases of naive B cells at those sites. It did not, however, drive the observed histopathological changes, which occurred independently also from major shifts in the lymphocyte-homing chemokines, CXCL12, CXCL13, and CCL19/21, as shown by quantitative reverse transcription-PCR (qRT-PCR), flow cytometry, and transwell migration experiments. Thus, B. burgdorferi infection drives the production of type I IFN in lymph nodes and in so doing strongly alters the cellular composition of the lymph nodes, with potential detrimental effects for the development of robust Borrelia-specific immunity.

Elevation in type I interferons inhibits HCN1 and slows cortical neuronal oscillations.

Central nervous system (CNS) inflammation involves the generation of inducible cytokines such as interferons (IFNs) and alterations in brain activity, yet the interplay of both is not well understood. Here, we show that in vivo elevation of IFNs by viral brain infection reduced hyperpolarization-activated currents (Ih) in cortical pyramidal neurons. In rodent brain slices directly exposed to type I IFNs, the hyperpolarization-activated cyclic nucleotide (HCN)-gated channel subunit HCN1 was specifically affected. The effect required an intact type I receptor (IFNAR) signaling cascade. Consistent with Ih inhibition, IFNs hyperpolarized the resting membrane potential, shifted the resonance frequency, and increased the membrane impedance. In vivo application of IFN-ß to the rat and to the mouse cerebral cortex reduced the power of higher frequencies in the cortical electroencephalographic activity only in the presence of HCN1. In summary, these findings identify HCN1 channels as a novel neural target for type I IFNs providing the possibility to tune neural responses during the complex event of a CNS inflammation.

The role of interferons in early pregnancy.

The interferons (IFNs) form part of the large family of glycoproteins known as cytokines. They are secreted by host cells as a line of defence against pathogens and certain tumours. IFNs affect cell proliferation and differentiation and also play a very important role in the functioning of the immune system. Miscarriage in both humans has been associated with higher levels of IFN, particularly IFN-γ. However, this cytokine is evidently vital in successful murine pregnancies since it is involved in maintaining the decidual layer in addition to remodelling of the vasculature in the uterus. The effects of IFN on human pregnancies are more difficult to study. Hence, there is still a lot more to be discovered in the hope of reaching a definite conclusion regarding the impact of IFN.

Hepatitis C virus replication in mouse cells is restricted by IFN-dependent and -independent mechanisms.

BACKGROUND & AIMS: Current treatment strategies for hepatitis C virus (HCV) infection include pegylated interferon (IFN)-alfa and ribavirin. Approximately 50% of patients control HCV infection after treatment, but the broad range of patients' outcomes and responses to treatment, among all genotypes, indicates a role for host factors. Although the IFN system is important in limiting HCV replication, the virus has evolved mechanisms to circumvent the IFN response. However, direct, IFN-independent antiviral processes also might help control HCV replication. We examined the role of IFN-independent responses against HCV replication. METHODS: We analyzed replication of the subgenomic JFH1 replicon in embryonic fibroblasts and primary hepatocytes from mice with disruptions in genes encoding factors in the IFN-dependent and alternative antiviral pathways (signal transducers and activators of transcription 1 [STAT1], protein kinase R, interferon regulatory factors (IRF) IRF-1, IRF-3, IRF-5, IRF-7, mitochondrial antiviral signaling molecule [MAVS], and IFN receptor [IFNAR]). We also assessed the effects of expression of these factors by mouse primary hepatocytes on HCV replication. RESULTS: In addition to IRF-3- and IFN-mediated antiviral responses, IFN-independent, but IRF-1- and IRF-5-dependent mechanisms, restrict HCV replication in mouse embryonic fibroblasts. In primary hepatocytes these IFN-independent require MAVS and IRF-1. CONCLUSIONS: HCV replication is limited by interferon-mediated pathways as well pathways that are independent of type I IFNs. IRF1 and IRF5 control IFN-independent signaling events that lead to antiviral responses. We observed antiviral roles of IRF1 and IRF5 that were IFN-independent and cell-type specific. These mechanisms are important in controlling viruses that interfere with the IFN signaling because cells retain the ability to induce functional but local antiviral states through expression of interferon-stimulated genes.