Interferon Αβ Research Articles

Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection.

SummaryThe outbreak of coronavirus disease 2019 (COVID‐19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID‐19 cases have been reported in 185 countries. Some patients with COVID‐19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS‐CoV‐2 infection as well as immunotherapeutic strategies for COVID‐19. Immune evasion by SARS‐CoV‐2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS‐CoV‐2 infection. Some potential immunotherapeutic strategies to control the progression of COVID‐19, such as passive antibody therapy and use of interferon αβ and IL‐6 receptor (IL‐6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID‐19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.

Mouse Models for Immunology Research available from The Jackson Laboratory Repository

Abstract The Jackson Laboratory Repository serves as a centralized facility for the development, distribution and cryopreservation of mouse models of human biology and disease. Hundreds of new strains are added annually to one of the largest collections of characterized mouse strains available. Our newest strains carry genes associated with T lymphocyte regulation and development. T cells from the Fyb (ADAP) knockout (KO) exhibit impaired proliferation and TCR-mediated adhesion. T cells from the Cd27 KO have a diminished viral response and a delayed memory cell response. A conditional KO of Kdm6b (Jmjd3), a histone demethylase, results in altered T cell differentiation. Finally, conditional expression of an HA-tagged mutant human transcription factor, FOXO, is associated with regulatory T cell function. Mice carrying the Ifnar1 (interferon αβ receptor 1) KO allele have a reduced immune response and increased susceptibility to viral infection. The Ifnar1 KO, combined with the Ifngr1 (interferon γ receptor 1) KO allele provide a model for Zika virus (and other viruses) pathogenesis. New tool strains include two conditional GFP knockin reporters, one in Spic, a transcription factor expressed in macrophages, and the second in Ebf1, a transcription factor involved in B cell development. A knockin to Zbtb46, a zinc finger transcription factor, expresses Cre recombinase in classical dendritic cells. Donating a strain to the Repository fulfills the NIH’s requirements for sharing mice. Researchers wishing to have strains considered for inclusion in the Repository are encouraged to submit their strains: www.jax.org/donate-a-mouse. This work is supported by NIH, HHMI, and several private charitable foundations.

Pathogenic potential of interferon αβ in acute influenza infection.

Influenza symptoms vary from mild disease to death; however, determinants of severity are unclear. Type I interferons (IFNαβ) are recognized as key antiviral cytokines. Here we show that, surprisingly, influenza-infected 129 mice have increased lung damage, morbidity and mortality, yet higher levels of IFNαβ, than C57BL/6 mice. Consistently, IFNα treatment of influenza-infected C57BL/6 mice increases morbidity. IFNαβ receptor deficiency in 129 mice decreases morbidity, lung damage, proinflammatory cytokines and lung-infiltrating inflammatory cells, and reduces expression of the death-inducing receptor DR5 on lung epithelia and its ligand TRAIL on inflammatory monocytes. Depletion of PDCA-1+ cells or interruption of TRAIL-DR5 interaction protects infected 129 mice. Selective lack of IFNαβ signalling in stromal cells abolishes epithelial DR5 upregulation and apoptosis, reducing host susceptibility. Hence, excessive IFNαβ signalling in response to acute influenza infection can result in uncontrolled inflammation and TRAIL-DR5-mediated epithelial cell death, which may explain morbidity and has important implications for treatment of severe disease.

Ebolavirus VP35 suppresses IFN production from conventional but not plasmacytoid dendritic cells

Ebolaviruses naturally infect a wide variety of cells including macrophages and dendritic cells (DCs), and the resulting cytokine and interferon-α/β (IFN) responses of infected cells are thought to influence viral pathogenesis. The VP35 protein impairs RIG-I-like receptor-dependent signaling to inhibit IFN production, and this function has been suggested to promote the ineffective host immune response characteristic of ebolavirus infection. To assess the impact of VP35 on innate immunity in biologically relevant primary cells, we used a recombinant Newcastle disease virus encoding VP35 (NDV/VP35) to infect macrophages and conventional DCs, which primarily respond to RNA virus infection via RIG-I-like pathways. VP35 suppressed not only IFN but also tumor necrosis factor (TNF)-α secretion, which are normally produced from these cells upon NDV infection. Additionally, in cells susceptible to the activity of VP35, IRF7 activation is impaired. In contrast, NDV/VP35 infection of plasmacytoid DCs, which activate IRF7 and produce IFN through TLR-dependent signaling, leads to robust IFN production. When plasmacytoid DCs deficient for TLR signaling were infected, NDV/VP35 was able to inhibit IFN production. Consistent with this, VP35 was less able to inhibit TLR-dependent versus RIG-I-dependent signaling in vitro. These data demonstrate that ebolavirus VP35 suppresses both IFN and cytokine production in multiple primary human cell types. However, cells that utilize the TLR pathway can circumvent this inhibition, suggesting that the presence of multiple viral sensors enables the host to overcome viral immune evasion mechanisms.

Organ-specific and differential requirement of TYK2 and IFNAR1 for LPS-induced iNOS expression in vivo

Lipopolysaccharide (LPS) is an integral structural component of the outer membrane of Gram-negative bacteria and the principal active agent in the pathogenesis of endotoxin shock. LPS is a potent inducer of a variety of cytokines and inflammatory agents that lead to a profound alteration of gene expression patterns in cells and organs. The gene coding for the inducible nitric oxide synthase (iNOS) is highly responsive to LPS in vitro and in vivo and accounts for the production of nitric oxide (NO). The Janus kinase (JAK) family member tyrosine kinase 2 (TYK2) is a constituent of the interferon (IFN) type I response pathway and an important effector in the progression of endotoxin shock. Macrophages deficient for IFN αβ receptor chain 1 (IFNAR1) or TYK2 were shown to have an impaired LPS-induced iNOS expression. Here we determined the contribution of IFNAR1 and TYK2 to iNOS expression in vivo in a lethal LPS challenge model. TYK2 and IFNAR1 were found to be crucial for the LPS-induced iNOS mRNA and protein expression in spleen and lung that could be attributed to the Mac3-positive population. In liver LPS-induced iNOS mRNA expression was only partially impaired in TYK2-deficient mice and was unimpaired in IFNAR1-deficient mice, indicating organ specificity. TYK2 −/− and IFNAR1 −/− mice also differ with respect to IFN γ production upon LPS challenge in that TYK2 −/− mice show a defect while IFNAR1 −/− mice do not. Our data suggest that iNOS is induced through IFNAR1 and TYK2 in Mac3-positive cells which are the main source of iNOS in spleen and lung. The LPS-induced iNOS expression in liver is independent of IFNAR1 and partially dependent on TYK2, which is most likely due to the lack of IFN γ production in the absence of TYK2.

No genetic linkage between multiple sclerosis and the interferon [formula omitted] locus

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 αβ locus and the development of MS. Based on our data, we conclude that there is no linkage between the Interferon αβ locus and MS.

Cloning and Expression of a Long Form of the β Subunit of the Interferon αβ Receptor That Is Required for Signaling

The interferon alpha beta receptor (IFN alpha R) or type I IFN-R is formed by a 110-kDa alpha subunit or IFNAR and by a beta subunit, which has short and long forms (molecular masses of 55 and 95-100 kDa, respectively). In this report, we demonstrate that the IFN alpha/beta R cDNA recently cloned corresponds to the 55-kDa or short form of the beta subunit, while the 95-100-kDa species reported here corresponds to a longer form of the IFN alpha/beta R cDNA that is probably produced by alternative splicing of the same gene. Stable transfection of the alpha subunit with either form of the beta subunit results in the expression of low and high affinity receptors, while expression of either form of the beta subunit alone only produces low affinity receptors. More important, only expression of the alpha and long form of the human beta subunits in mouse L-929 cells reconstitutes the activation of the Jak kinases and the Stat factors, as well as the antiviral response to human type I IFNs.

Neutrophil-macrophage Interaction: a paradigm for chronic inflammation

Autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease are characterized by chronic inflammatory responses resulting in tissue damage. These diseases have a number of common denominators including: abnormal cytokine expression, aberrant antigen-antibody complexes, T cell anomalies, and increased numbers of neutrophils and macrophages. We propose that the interaction between neutrophils and macrophages induces a state of chronic inflammation which contributes to the disease state. One of the central players in this scenario is myeloperoxidase (MyPo). This enzyme functions in the ‘cytotoxic triad’ and is involved in cell killing. Studies done by the present investigators have shown that MyPo, which is released from neutrophils, induces macrophages to secrete interleukin-1, interferon αβ and tumor necrosis factor α. Furthermore, our studies have suggested a major immunoregulatory role of this enzyme. We propose that the release of MyPo from neutrophils and subsequent binding to macrophages initiates a cascade of events which enhance the production of reactive oxygen intermediates and cytokine expression resulting in the chronic inflammatory state associated with autoimmune diseases.

Structure of the murine interferon alpha/beta receptor-encoding gene: high-frequency rearrangements in the interferon-resistant L1210 cell line.

The structure of the murine IFNAR gene, encoding the interferon alpha/beta receptor, is reported. The gene has eleven exons dispersed in about 23 kb of genomic DNA. The nature of the rearrangements affecting this gene in interferon-resistant (IFNR) L1210 mutant cell lines is described.

Murine tumor cells expressing the gene for the human interferon αβ receptor elicit antibodies in syngeneic mice to the active form of the receptor

The cellular receptor for the human alpha and beta interferons (IFN) was expressed, by gene transfer, in a murine hepatoma-derived cell line, BTG 9A. Injected subcutaneously into the syngeneic mouse (C57BL/6), the parental and the transfected cells grew and formed tumors which later regressed. More than half the mice bearing tumors derived from cells expressing the receptor, developed IgG antibodies capable of blocking the activity, on human cells, of human recombinant IFN-alpha B, -alpha A, -alpha D and of natural human IFN-beta, but not of recombinant IFN-gamma. Cross-reactivity of human IFN-alpha on murine and bovine cells was unaffected by these antibodies. The binding of human IFN-alpha to solubilized receptors from human lymphoid cell lines was also blocked and complexes of radiolabeled recombinant IFN-alpha A or IFN-alpha B, chemically cross-linked to their human receptor could be immunoprecipitated by the antisera. IFN alpha beta receptor protein, purified by electrophoresis in sodium dodecylsulfate, was not recognized. We conclude that the antibodies are directed against the forms of the IFN alpha beta receptor actually expressed on the membrane.

Interferon-induced protein Mx accumulates in nuclei of mouse cells expressing resistance to influenza viruses

In mouse cells carrying the dominant influenza resistance allele M x + (but not in M x − cells) interferon-α/β (IFN) induces an efficient antiviral state against influenza viruses and, concomitantly, the synthesis of a 75,000-Da protein (protein Mx). Here, indirect immunofluorescence using monoclonal antibodies was used to demonstrate that protein Mx accumulates in the nucleus of IFN-treated M x + cells, suggesting a nuclear site of action. Protein Mx is present in the nucleus of untreated influenza virus-resistant macrophages freshly explanted from the peritoneal cavity of M x + mice but is lost with time in culture when peritoneal macrophages become permissive for influenza virus.

Effects of splenectomy on production of endotoxin-type interferon in mice

When C3H/He mice were treated with lipopolysaccharide, poly(I) · poly(C), or pokeweed mitogen, the serum interferon titer increased almost instantaneously (100–2000 units/ml), and then the pulmonary indoleamine 2,3-dioxygenase was induced 50- to 140-fold. The peaks corresponding to interferon induction always preceded (approximately 24 h) those corresponding to dioxygenase induction. In C3H/HeJ (lipopolysaccharide-nonresponder) mice, however, lipopolysaccharide was totally inert in induction of both interferon and dioxygenase, although treatment with poly(I) · poly(C) and pokeweed mitogen led to a remarkable increase in the serum interferon titer and the enzyme activity. When lymphocytes of C3H/He mice were inactivated by X irradiation and then reconstituted by the transfer of spleen cells from C3H/He mice, both enzyme and interferon from C3H/HeJ mice thus treated were induced almost normally after the lipopolysaccharide treatment. In addition, murine interferon αβ, which was injected intravenously in C3H/He or C3H/HeJ mice, almost instantaneously and dose-dependently induced the pulmonary enzyme, and at a dose of 105 units per mouse the enzyme activity was enhanced 20- to 26-fold in these two strains of mice. These results suggest that interferon, which is generated by the interaction of lymphocytes with lipopolysaccharide, poly(I) · poly(C), or pokeweed mitogen, is a mediator of indoleamine 2,3-dioxygenase induction in the mouse lung by these agents.