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Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-β secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-β immunity. ispartof: JOURNAL OF CLINICAL INVESTIGATION vol:131 issue:1 ispartof: location:United States status: published

We previously showed that in mice infected with Leishmania major type I interferons (IFNs) initiate the innate immune response to the parasite at day 1 and 2 of infection. Here, we investigated which type I IFN subtypes are expressed during the first 8 weeks of L. major infection and whether type I IFNs are essential for a protective immune response and clinical cure of the disease. In self-healing C57BL/6 mice infected with a high dose of L. major, IFN-α4, IFN-α5, IFN-α11, IFN-α13, and IFN-β mRNA were most prominently regulated during the course of infection. In C57BL/6 mice deficient for IFN-β or the IFN-α/β-receptor chain 1 (IFNAR1), development of skin lesions and parasite loads in skin, draining lymph node, and spleen was indistinguishable from wild-type (WT) mice. In line with the clinical findings, C57BL/6 IFN-β−/−, IFNAR1−/−, and WT mice exhibited similar mRNA expression levels of IFN-γ, interleukin (IL)-4, IL-12, IL-13, inducible nitric oxide synthase, and arginase 1 during the acute and late phase of the infection. Also, myeloid dendritic cells from WT and IFNAR1−/− mice produced comparable amounts of IL-12p40/p70 protein upon exposure to L. major in vitro. In non-healing BALB/c WT mice, the mRNAs of IFN-α subtypes (α2, α4, α5, α6, and α9) were rapidly induced after high-dose L. major infection. However, genetic deletion of IFNAR1 or IFN-β did not alter the progressive course of infection seen in WT BALB/c mice. Finally, we tested whether type I IFNs and/or IL-12 are required for the prophylactic effect of CpG-oligodesoxynucleotides (ODN) in BALB/c mice. Local and systemic administration of CpG-ODN 1668 protected WT and IFN-β−/− mice equally well from progressive leishmaniasis. By contrast, the protective effect of CpG-ODN 1668 was lost in BALB/c IFNAR1−/− (despite a sustained suppression of IL-4) and in BALB/c IL-12p35−/− mice. From these data, we conclude that IFN-β and IFNAR1 signaling are dispensable for a curative immune response to L. major in C57BL/6 mice and irrelevant for disease development in BALB/c mice, whereas IL-12 and IFN-α subtypes are essential for the disease prevention by CpG-ODNs in this mouse strain.

▪ Abstract The significance of type I interferons (IFN-α/β) in biology and medicine renders research on their activities continuously relevant to our understanding of normal and abnormal (auto) immune responses. This relevance is bolstered by discoveries that unambiguously establish IFN-α/β, among the multitude of cytokines, as dominant in defining qualitative and quantitative characteristics of innate and adaptive immune processes. Recent advances elucidating the biology of these key cytokines include better definition of their complex signaling pathways, determination of their importance in modifying the effects of other cytokines, the role of Toll-like receptors in their induction, their major cellular producers, and their broad and diverse impact on both cellular and humoral immune responses. Consequently, the role of IFN-α/β in the pathogenesis of autoimmunity remains at the forefront of scientific inquiry and has begun to illuminate the mechanisms by which these molecules promote or inhibit systemic and organ-specific autoimmune diseases.

The two classes of interferons, type I (IFNα, IFNβ, IFNω, and IFNτ) and type II (IFNλ) are pleiotropic cytokines that exhibit antiviral, antiproliferative, and immunomodulatory effects on their target cells. This article summarizes the advances made in elucidating the molecular events that mediate the biological responses to type I interferons.

Tumors that develop in immunocompetent hosts show reduced immunogenicity because of selective pressure to escape destruction by immune cells. Type I interferons are involved in shaping this evasive response but, unexpectedly, tumor cells are not the main targets of these interferons.

Peritoneal macrophages (Mo) constitutively synthesize and secrete interferon-α (IFN-α) and IFN-β, as well as complement subcomponent Clq. Because exogenous interferon-γ (IFN-γ) stimulates Mo synthe...

A model for reliable estimation of variance components for biological within- and between-subject variation as well as for analytical variation when both the quantity and the reagents are unstable has been established. This model was applied to the alpha-interferon receptor on human leucocytes which involves two major problems. First, the receptor has to be quantified within a few hours after blood sampling, and second, the reagents for the measurement procedure must be used within 2 weeks. For the number of receptors per cell the biological estimates of coefficients of variation were 14% for within-subject variation and 20% for between-subject variation, respectively. For the dissociation constant both estimates were zero as expected. The model is robust and applicable to other systems with unstable quantities and reagents.

The concept of ‘innate immunity’ embraces all sorts of measures that exclude, inhibit, or slow down infections with little specificity and without adaptation or generation of a protective memory. The mammalian innate immune defenses described in this article comprise the complement system, nonspecific phagocytic and cytolytic leukocytes (macrophages, monocytes, granulocytes, natural killer cells, and dendritic cells), and cytokines such as the antivirally active type I interferons. Since the type I interferon (IFN-α/β) system is our primary defense against viral infections, special attention will be paid to the virus-triggered induction of IFN transcription, the signaling activated by IFNs, and the antiviral factors expressed as a consequence.

Biological systems have acquired adaptability and robustness against rapid environmental changes. A typical example is the immune system, which eradicates invading pathogens such as viruses. Interferons alpha and beta, which are produced in response to viral infection, are essential components of this system but are also produced at low levels in the absence of infection. What is the purpose of the constitutive weak interferon-alpha/beta signal?

Multiple sclerosis (MS) is probably caused by an interaction of genetic and environmental factors. The genetic component is reflected by a ten-fold higher concordance rate in monozygotic (27%) compared to dizygotic (3%) twin pairs. Treatment with interferon was recently reported to have a favorable effect in patients with relapsing-remitting MS. In the present familial study, we have investigated the possibility of a genetic association between the highly polymorphic Interferon alpha beta locus and the development of MS. Based on our data, we conclude that there is no linkage between the Interferon alpha beta locus and MS.

Interferon-alpha/beta (IFN-alpha/beta) suppresses cell cycle activation by platelet-derived growth factor (PDGF) as well as the induction of the 31-kD (pI) and the 35-kD (pII) proteins in density-arrested BALB/c-3T3 cells. We report that elevation of [Ca2+]i by ionomycin induces the synthesis of the 31-kD protein, but not that of the 35-kD protein. Since IFN blocks the PDGF-induced elevation of [Ca2+]i, these results suggest that IFN treatment may suppress pI induction by impairing this PDGF-activated signal transduction pathway. In contrast, because ionomycin did not induce the 35-kD protein, the suppression by IFN of PDGF-induced pII appears to be mediated via a pathway distinct from that operating in the suppression of pI. In BALB/c-3T3 cells, IFN-alpha/beta did not itself affect the turnover or de novo synthesis of inositol phospholipids and the cellular content of diacylglycerol, nor did IFN block the enhancement of these parameters by PDGF.

Rauscher murine leukemia virus (R-MuLV) induces a rapidly developing erythroleukemia in BALB/c mice. Previously, we have shown that mouse interferon-alpha/beta (Mu IFN-alpha/beta) applied shortly after virus inoculation efficiently inhibits the leukemic process (Hekman et al., 1981). Here we describe the effect of Mu IFN-alpha/beta on an established leukemia. Varying doses of Mu IFN-alpha/beta were injected over 3 days, starting 8 to 12 days after virus inoculation. The effect of Mu IFN-alpha/beta on the leukemic process was monitored by measuring the spleen weight, reverse transcriptase activity in the serum and, in selected experiments, by microscopic examination of sections of the spleen using standard histological and immunological staining techniques. Depending on the spleen weight at the start of its application (maximal about 450 mg), Mu IFN-alpha/beta caused a dramatic reduction in the number of virus-infected erythroleukemic cells in the spleen. Also, R-MuLV disappeared from the serum within 3 days. If Mu IFN-alpha/beta was injected into R-MuLV-infected mice with an already 10-fold enlarged spleen, it could only stop further development of leukemia. Results obtained with crude Mu IFN-alpha/beta preparations were confirmed with absolutely pure Mu IFN-beta.

The highly metastatic ESb tumor is totally resistant to murine interferon-alpha/beta (IFN-alpha/beta) therapy, regardless of the number of cells injected or the route of inoculation. In contrast, as we show herein, mouse IFN-alpha1-transduced ESb tumor cells were inhibited markedly when injected subcutaneously into immunocompetent mice. IFN-producing ESb tumor rejection was mediated by the immune system, because these tumor cells grew normally in immunosuppressed mice. Tumor regression was accompanied by extensive necrosis and cellular infiltrates in the tumor area. These results further support the use of IFN-alpha in cytokine gene therapy of cancer and suggest the advantage of using gene transfer rather than cytokine administration to enhance an antitumor immune response.