48 results on '"Gad, Hans Henrik"'
Search Results
2. Establishment of well-differentiated camelid airway cultures to study Middle East respiratory syndrome coronavirus
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Gultom, Mitra, Kratzel, Annika, Portmann, Jasmine, Stalder, Hanspeter, Chanfon Bätzner, Astrid, Gantenbein, Hans, Gurtner, Corinne, Ebert, Nadine, Gad, Hans Henrik, Hartmann, Rune, Posthaus, Horst, Zanolari, Patrik, Pfaender, Stephanie, Thiel, Volker, and Dijkman, Ronald
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- 2022
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3. Two cGAS-like receptors induce antiviral immunity in Drosophila
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Holleufer, Andreas, Winther, Kasper Grønbjerg, Gad, Hans Henrik, Ai, Xianlong, Chen, Yuqiang, Li, Lihua, Wei, Ziming, Deng, Huimin, Liu, Jiyong, Frederiksen, Ninna Ahlmann, Simonsen, Bine, Andersen, Line Lykke, Kleigrewe, Karin, Dalskov, Louise, Pichlmair, Andreas, Cai, Hua, Imler, Jean-Luc, and Hartmann, Rune
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- 2021
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4. Defective interferon priming and impaired antiviral responses in a patient with an IRF7 variant and severe influenza
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Thomsen, Michelle M., Jørgensen, Sofie E., Gad, Hans Henrik, Storgaard, Merete, Gjedsted, Jakob, Christiansen, Mette, Hartmann, Rune, and Mogensen, Trine H.
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- 2019
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5. Interferon-λ enhances adaptive mucosal immunity by boosting release of thymic stromal lymphopoietin
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Ye, Liang, Schnepf, Daniel, Becker, Jan, Ebert, Karolina, Tanriver, Yakup, Bernasconi, Valentina, Gad, Hans Henrik, Hartmann, Rune, Lycke, Nils, and Staeheli, Peter
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- 2019
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6. Viral recognition and the antiviral interferon response.
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Dalskov, Louise, Gad, Hans Henrik, and Hartmann, Rune
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TYPE I interferons , *INTERFERONS , *VIRUS diseases , *INTERFERON regulatory factors , *IMMUNE response , *VIRAL replication - Abstract
Interferons (IFNs) are antiviral cytokines that play a key role in the innate immune response to viral infections. In response to viral stimuli, cells produce and release interferons, which then act on neighboring cells to induce the transcription of hundreds of genes. Many of these gene products either combat the viral infection directly, e.g., by interfering with viral replication, or help shape the following immune response. Here, we review how viral recognition leads to the production of different types of IFNs and how this production differs in spatial and temporal manners. We then continue to describe how these IFNs play different roles in the ensuing immune response depending on when and where they are produced or act during an infection. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Chikungunya Virus Envelope Protein E2 Provides a Vector for Targeted Antigen Delivery to Human Dermal CD14+ Dendritic Cells
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Brulefert, Adrien, Kraemer, Melanie, Cumin, Marie, Selle, Amandine, Hoste, Astrid, Gad, Hans-Henrik, Rühl, Julia, Madinier, Jean-Baptiste, Chaloin, Olivier, Münz, Christian, Desprès, Philippe, Mueller, Christopher George, and Flacher, Vincent
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- 2021
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8. Cryo‐EM structure of the human NKCC1 transporter reveals mechanisms of ion coupling and specificity.
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Neumann, Caroline, Rosenbæk, Lena Lindtoft, Flygaard, Rasmus Kock, Habeck, Michael, Karlsen, Jesper Lykkegaard, Wang, Yong, Lindorff‐Larsen, Kresten, Gad, Hans Henrik, Hartmann, Rune, Lyons, Joseph Anthony, Fenton, Robert A, and Nissen, Poul
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MOLECULAR dynamics ,GLUTAMATE transporters ,CELL membranes ,POTASSIUM channels ,CENTRAL nervous system ,X-ray crystallography ,IONS ,CHLORIDE channels - Abstract
The sodium–potassium–chloride transporter NKCC1 of the SLC12 family performs Na+‐dependent Cl−‐ and K+‐ion uptake across plasma membranes. NKCC1 is important for regulating cell volume, hearing, blood pressure, and regulation of hyperpolarizing GABAergic and glycinergic signaling in the central nervous system. Here, we present a 2.6 Å resolution cryo‐electron microscopy structure of human NKCC1 in the substrate‐loaded (Na+, K+, and 2 Cl−) and occluded, inward‐facing state that has also been observed for the SLC6‐type transporters MhsT and LeuT. Cl− binding at the Cl1 site together with the nearby K+ ion provides a crucial bridge between the LeuT‐fold scaffold and bundle domains. Cl−‐ion binding at the Cl2 site seems to undertake a structural role similar to conserved glutamate of SLC6 transporters and may allow for Cl−‐sensitive regulation of transport. Supported by functional studies in mammalian cells and computational simulations, we describe a putative Na+ release pathway along transmembrane helix 5 coupled to the Cl2 site. The results provide insight into the structure–function relationship of NKCC1 with broader implications for other SLC12 family members. Synopsis: The Na+‐K+‐2Cl− cotransporter NKCC1 (SLC12A2) performs Na+‐dependent uptake of Cl− and K+ ions and is an important factor in ion homeostasis and osmotic control. Its mechanisms of ion recognition and release are addressed here by cryo‐EM microscopy, ion uptake studies, and molecular dynamics simulations. A 2.6 Å resolution cryo‐EM map reveals lipid molecules at a dimeric interface and three cholesterol molecules per protomer that regulate its transport activity.Analysis of the revealed intracellular water networks and bound ions indicates that the Cl– ion at a Cl2 site is released reversibly prior to Na+ release.Intracellular Na+ ion release is modeled and indicates guidance along transmembrane helix 5 by two negatively charged glutamate residues.The Cl2 site, which overlaps with a conserved glutamate residue in the SLC6 transporter, may sense chloride to regulate transport. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Comparing the stability and activity of recombinant IFNλ3 and IFNλ4: ID: 191
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Gad, Hans Henrik, Christensen, Kasper Thorhauge, Terczyńska-Dyla, Ewa, and Hartmann, Rune
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- 2015
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10. Investigating the role of interferon λ4 in hepatitis C virus infection: ID: 101
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Terczynska-Dyla, Ewa, Bibert, Stephanie, Duong, Francois H.T., Lauber, Chris, Gad, Hans Henrik, Kaderali, Lars, Heim, Markus H., Bochud, Pierre-Yves, and Hartmann, Rune
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- 2015
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11. A novel role for the oligoadenylate synthetase-like protein in viral recognition and interferon induction: 85
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Gad, Hans Henrik, Ibsen, Mikkel S., Andersen, Line L., Hornung, Veit, Sarka, Saumendra N., and Hartmann, Rune
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- 2013
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12. Mapping the active site and investigating the polyI:C inducibility of the human 120 kDa 2’-5’ Oligoadenylate Synthetase 3: PS2-008
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Ibsen, Mikkel, Gad, Hans Henrik, Despres, Philippe, and Hartmann, Rune
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- 2011
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13. The battle between host and virus: how chikungunya virus is inhibited by 2′-5′-oligoadenylate synthetases and how it may escape the battle: SS10-7
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Gad, Hans Henrik, Paulous, Sylvie, Caro, Valerie, Hartmann, Rune, Kümmerer, Beate, and Despres, Philippe
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- 2010
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14. 220 Antiviral potency of interferon lambda and identification of amino acids that are important for the antiviral activity of interferon Lambda II
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Gad, Hans Henrik, Dellgren, Christoffer, Hamming, Ole J., Vends, Susanne, and Hartmann, Rune
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- 2008
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15. Interferon-λ Improves the Efficacy of Intranasally or Rectally Administered Influenza Subunit Vaccines by a Thymic Stromal Lymphopoietin-Dependent Mechanism.
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Ye, Liang, Schnepf, Daniel, Ohnemus, Annette, Ong, Li Ching, Gad, Hans Henrik, Hartmann, Rune, Lycke, Nils, and Staeheli, Peter
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INFLUENZA vaccines ,T helper cells ,THYMIC stromal lymphopoietin ,GERMINAL centers ,CELL migration - Abstract
Previous work showed that interferon-λ (IFN-λ) can trigger the synthesis of thymic stromal lymphopoietin (TSLP) by specialized epithelial cells in the upper airways of mice, thereby improving the performance of intranasally administered influenza vaccines. Here we demonstrate that protein-only influenza vaccines containing either IFN-λ or TSLP boosted antigen-specific IgG1 and IgA responses and enhanced the resistance of mice to influenza virus challenge, irrespective of whether the vaccines were applied via the intranasal or the rectal route. TSLP receptor deficiency negatively influenced vaccine-induced antiviral immunity by impairing the migration of dendritic cells from the airways to the draining lymph nodes of immunized mice, thereby restraining follicular helper T cell and germinal center B cell responses. As previously observed during intranasal vaccination, the adjuvant effect of IFN-λ on a rectally administered influenza vaccine was no longer observed when TSLP receptor-deficient mice were used for immunization, highlighting the central role of the IFN-λ/TSLP axis for vaccine-induced antiviral immunity in the mucosa. [ABSTRACT FROM AUTHOR]
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- 2021
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16. Selective Janus kinase inhibition preserves interferon-λ–mediated antiviral responses.
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Schnepf, Daniel, Crotta, Stefania, Thamamongood, Thiprampai, Stanifer, Megan, Polcik, Laura, Ohnemus, Annette, Vier, Juliane, Jakob, Celia, Llorian, Miriam, Gad, Hans Henrik, Hartmann, Rune, Strobl, Birgit, Kirschnek, Susanne, Boulant, Steeve, Schwemmle, Martin, Wack, Andreas, and Staeheli, Peter
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Specific inhibition: Janus kinase (JAK) inhibitors are powerful therapeutics used to treat inflammatory diseases but are also linked to immune suppression and complications associated with viral infections. Schnepf et al. show that selective inhibition of tyrosine kinase 2 (TYK2) can block potentially noxious type I IFN signaling but does not alter IFN-λ signaling, whereas the JAK1/2 inhibitor baricitinib blocks both types of IFN responses. Epithelial cells did not require TYK2 for IFN-λ–driven gene expression or antiviral responses, and TYK2-deficient mice have intact IFN-λ–mediated responses and are protected from influenza A virus infection. These findings indicate that TYK2 inhibition may be a better treatment option for type I interferonopathies. Inflammatory diseases are frequently treated with Janus kinase (JAK) inhibitors to diminish cytokine signaling. These treatments can lead to inadvertent immune suppression and may increase the risk of viral infection. Tyrosine kinase 2 (TYK2) is a JAK family member required for efficient type I interferon (IFN-α/β) signaling. We report here that selective TYK2 inhibition preferentially blocked potentially detrimental type I IFN signaling, whereas IFN-λ–mediated responses were largely preserved. In contrast, the clinically used JAK1/2 inhibitor baricitinib was equally potent in blocking IFN-α/β– or IFN-λ–driven responses. Mechanistically, we showed that epithelial cells did not require TYK2 for IFN-λ–mediated signaling or antiviral protection. TYK2 deficiency diminished IFN-α–induced protection against lethal influenza virus infection in mice but did not impair IFN-λ–mediated antiviral protection. Our findings suggest that selective TYK2 inhibitors used in place of broadly acting JAK1/2 inhibitors may represent a superior treatment option for type I interferonopathies to counteract inflammatory responses while preserving antiviral protection mediated by IFN-λ. [ABSTRACT FROM AUTHOR]
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- 2021
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17. 2′3′-cGAMP triggers a STING- and NF-κB–dependent broad antiviral response in Drosophila.
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Cai, Hua, Holleufer, Andreas, Simonsen, Bine, Schneider, Juliette, Lemoine, Aurélie, Gad, Hans Henrik, Huang, Jingxian, Huang, Jieqing, Chen, Di, Peng, Tao, Marques, João T., Hartmann, Rune, Martins, Nelson E., and Imler, Jean-Luc
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DROSOPHILA ,SMALL interfering RNA ,TYPE I interferons ,INTERFERON receptors ,GENETIC mutation ,TRANSCRIPTION factors ,VIRUS diseases - Abstract
STINGing viruses without interferon: The adaptor protein STING induces the production of antiviral interferons in response to the cyclic dinucleotide 2′3′-cGAMP generated as a "danger" signal during viral infection of mammalian cells. Drosophila have a STING ortholog but do not produce interferons. Cai et al. found that exogenously administered 2′3′-cGAMP protected Drosophila against multiple DNA and RNA viruses in a manner dependent on STING and the transcription factor Relish, an ortholog of NF-κB. This antiviral immunity did not involve autophagy, a cellular process in which STING plays an evolutionarily conserved role and that can restrict viral replication, or RNA interference, an antiviral response in Drosophila. These results suggest that 2′3′-cGAMP as a viral danger signal is evolutionarily older than previously suspected and that STING was incorporated into the interferon response during vertebrate evolution. We previously reported that an ortholog of STING regulates infection by picorna-like viruses in Drosophila. In mammals, STING is activated by the cyclic dinucleotide 2′3′-cGAMP produced by cGAS, which acts as a receptor for cytosolic DNA. Here, we showed that injection of flies with 2′3′-cGAMP induced the expression of dSTING-regulated genes. Coinjection of 2′3′-cGAMP with a panel of RNA or DNA viruses resulted in substantially reduced viral replication. This 2′3′-cGAMP–mediated protection was still observed in flies with mutations in Atg7 and AGO2, genes that encode key components of the autophagy and small interfering RNA pathways, respectively. By contrast, this protection was abrogated in flies with mutations in the gene encoding the NF-κB transcription factor Relish. Transcriptomic analysis of 2′3′-cGAMP–injected flies revealed a complex response pattern in which genes were rapidly induced, induced after a delay, or induced in a sustained manner. Our results reveal that dSTING regulates an NF-κB–dependent antiviral program that predates the emergence of interferons in vertebrates. [ABSTRACT FROM AUTHOR]
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- 2020
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18. Systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome due to a CASP1 variant causing inflammasome hyperactivation.
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Jørgensen, Sofie E, Christiansen, Mette, Høst, Christian, Glerup, Mia, Mahler, Birgitte, Lausten, Mira M, Gad, Hans Henrik, Hartmann, Rune, Herlin, Troels, and Mogensen, Trine H
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BIOMARKERS ,CYTOKINES ,INTERLEUKINS ,PROTEINS ,JUVENILE idiopathic arthritis ,DNA-binding proteins ,GENETIC markers ,MACROPHAGE activation syndrome ,LIPOPOLYSACCHARIDES ,CASPASES - Abstract
Objectives We investigated a patient with systemic juvenile idiopathic arthritis (sJIA) and recurrent macrophage activation syndrome (MAS) to discover genetic and immunological contributing factors. Methods Severe recurrent MAS motivated whole exome sequencing (WES) to identify genetic variants potentially involved in disease pathogenesis. In vitro peripheral blood mononuclear cell (PBMC) stimulations for cytokine expression and caspase-1 activity assays as well as NF-κB reporter luciferase assays were performed to functionally characterize variants. Results WES revealed an extremely rare heterozygous missense variant, c.482G>A, p.R161H in the CASP1 gene encoding pro-caspase-1. Lipopolysaccharide (LPS) stimulation of patient PBMCs induced high levels of IL-6 compared to controls, and activation of the NLRP3 inflammasome resulted in increased production of IL-1β and IL-18 as well as significantly elevated caspase-1 activity. Constitutive and inducible levels of IL-18 and IFNγ in whole blood were markedly elevated. Expression of the CASP1 variant in an NF-κB reporter luciferase assay induced increased NF-κB activation in a RIP2-dependent manner. The disease course of the patient was complicated by severe recurrent MAS. However, dual IL-1 and IL-6 blockade caused disease remission. Conclusion For the first time, we demonstrate the involvement of a CASP1 variant in sJIA and recurrent MAS. This variant is gain-of-function for both inflammasome and NF-κB activation leading to increased production of IL-6, IL-1β and IL-18. Although dual IL-1 and IL-6 blockade may be beneficial in patients, in whom single treatment is not sufficient to control MAS, caution should be practiced, since interstitial lung disease may progress despite apparent clinical and biochemical remission. [ABSTRACT FROM AUTHOR]
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- 2020
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19. Type I and III interferons disrupt lung epithelial repair during recovery from viral infection.
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Major, Jack, Crotta, Stefania, Llorian, Miriam, McCabe, Teresa M., Gad, Hans Henrik, Priestnall, Simon L., Hartmann, Rune, and Wack, Andreas
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- 2020
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20. Identification of an IRF3 variant and defective antiviral interferon responses in a patient with severe influenza.
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Thomsen, Michelle M., Jørgensen, Sofie E., Storgaard, Merete, Kristensen, Lasse S., Gjedsted, Jakob, Christiansen, Mette, Gad, Hans Henrik, Hartmann, Rune, and Mogensen, Trine H.
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INFLUENZA ,INTERFERONS - Abstract
Here we describe a patient, P1, a 55-year old Caucasian male with severe influenza A virus (IAV) infection, who was heterozygous for a variant in the 3'UTR of the transcription factor IRF3. GLO:BVO/01nov19:eji4600-fig-0002.jpg PHOTO (COLOR): Impaired antiviral responses to IAV and Nanostring analysis of differentially expressed immune genes in patient PBMCs. Here, we report the identification of a variant of the transcription factor IRF3 together with impaired antiviral IFN responses in an adult patient who developed severe life-threatening influenza infection during the H1N1 swine flu pandemic in 2009-2010. [Extracted from the article]
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- 2019
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21. The Influence of the rs30461 Single Nucleotide Polymorphism on IFN-λ1 Activity and Secretion.
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Møhlenberg, Michelle, Gad, Hans Henrik, and Hartmann, Rune
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SINGLE nucleotide polymorphisms , *SECRETION , *HUMAN evolution , *INTERFERONS , *LOCUS (Genetics) - Abstract
Genetic variation within the IFNL loci is associated with several diseases and evidence indicates that the IFNL genes have been subjects of strong selection during recent human evolution. The nonsynonymous rs30461 single nucleotide polymorphism (SNP), generating interferon (IFN)-λ1 D188N, shows a strong signature of positive selection in European and Asian populations. Nevertheless, genetic association studies have failed to show any coupling of rs30461 to diseases such as psoriasis and periodontitis. Based on these observations, we purified IFN-λ1 N188 and IFN-λ1 D188 to compare the biological activity of these 2 IFN-λ1 versions. Furthermore, we evaluated the secretion of the 2 different IFN-λ1 versions. We were unable to observe any differences between IFN-λ1 N188 and IFN-λ1 D188 based on biological activity or secretion that could account for the positive selection. [ABSTRACT FROM AUTHOR]
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- 2019
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22. Species Specificity of Type III Interferon Activity and Development of a Sensitive Luciferase-Based Bioassay for Quantitation of Mouse Interferon-λ.
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Jacobs, Sophie, Wavreil, Fanny, Schepens, Bert, Gad, Hans Henrik, Hartmann, Rune, Rocha-Pereira, Joana, Neyts, Johan, Saelens, Xavier, and Michiels, Thomas
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INTERFERONS ,LUCIFERASES ,ENZYME-linked immunosorbent assay ,ANTINEOPLASTIC agents ,ANTIVIRAL agents - Abstract
The type III interferon (IFN-λ) family includes 4 IFN-λ subtypes in man. In the mouse, only the genes coding for IFN-λ2 and -λ3 are present. Unlike mouse and human type I IFNs (IFN-α/β), which exhibit strong species specificity, type III IFNs were reported to act in a cross-specific manner. We reexamined the cross-specificity and observed that mouse and human IFN-λ exhibit some species specificity, although much less than type I IFNs. Mouse IFN-λ3 displayed clear species specificity, being 25-fold less active in human cells than the closely related mouse IFN-λ2. This specificity likely depends on amino acids in α helices A and F that diverged from other IFN-λ sequences. Human IFN-λ4, in contrast, retained high activity in mouse cells. We next developed a firefly luciferase-based reporter cell line, named Fawa-λ-luc, to detect IFN-λ in biological fluids with high specificity and sensitivity. Fawa-λ-luc cells, derived from mouse epithelial cells that are responsive to IFN-λ, were made nonresponsive to type I IFNs by inactivation of the Ifnar2 gene and strongly responsive to IFN-λ by overexpression of the mouse IFNLR1. This bioassay was as sensitive as a commercially available enzyme-linked immunosorbent assay in detecting mouse IFN-λ in cell culture supernatant, as well as in serum and bronchoalveolar lavage samples of virus-infected mice. The assay also enabled the sensitive detection of human IFN-λ activity, including that of the divergent IFN-λ4 with a bias, however, due to variable activity of IFN-λ subtypes. [ABSTRACT FROM AUTHOR]
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- 2018
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23. The interferon-stimulated gene product oligoadenylate synthetase-like protein enhances replication of Kaposi’s sarcoma-associated herpesvirus (KSHV) and interacts with the KSHV ORF20 protein.
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Bussey, Kendra A., Lau, Ulrike, Schumann, Sophie, Gallo, Antonio, Osbelt, Lisa, Stempel, Markus, Arnold, Christine, Wissing, Josef, Gad, Hans Henrik, Hartmann, Rune, Brune, Wolfram, Jänsch, Lothar, Whitehouse, Adrian, and Brinkmann, Melanie M.
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KAPOSI'S sarcoma-associated herpesvirus ,VIRAL proteins ,MASS spectrometry ,RIBOSOMAL proteins ,INTERFERONS ,OLIGOADENYLATE synthetase - Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is one of the few oncogenic human viruses known to date. Its large genome encodes more than 85 proteins and includes both unique viral proteins as well as proteins conserved amongst herpesviruses. KSHV ORF20 is a member of the herpesviral core UL24 family, but the function of ORF20 and its role in the viral life cycle is not well understood. ORF20 encodes three largely uncharacterized isoforms, which we found were localized predominantly in the nuclei and nucleoli. Quantitative affinity purification coupled to mass spectrometry (q-AP-MS) identified numerous specific interacting partners of ORF20, including ribosomal proteins and the interferon-stimulated gene product (ISG) oligoadenylate synthetase-like protein (OASL). Both endogenous and transiently transfected OASL co-immunoprecipitated with ORF20, and this interaction was conserved among all ORF20 isoforms and multiple ORF20 homologs of the UL24 family in other herpesviruses. Characterization of OASL interacting partners by q-AP-MS identified a very similar interactome to that of ORF20. Both ORF20 and OASL copurified with 40S and 60S ribosomal subunits, and when they were co-expressed, they associated with polysomes. Although ORF20 did not have a global effect on translation, ORF20 enhanced RIG-I induced expression of endogenous OASL in an IRF3-dependent but IFNAR-independent manner. OASL has been characterized as an ISG with antiviral activity against some viruses, but its role for gammaherpesviruses was unknown. We show that OASL and ORF20 mRNA expression were induced early after reactivation of latently infected HuARLT-rKSHV.219 cells. Intriguingly, we found that OASL enhanced infection of KSHV. During infection with a KSHV ORF20stop mutant, however, OASL-dependent enhancement of infectivity was lost. Our data have characterized the interaction of ORF20 with OASL and suggest ORF20 usurps the function of OASL to benefit KSHV infection. [ABSTRACT FROM AUTHOR]
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- 2018
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24. IFNλ is a potent anti-influenza therapeutic without the inflammatory side effects of IFNα treatment.
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Davidson, Sophia, McCabe, Teresa M, Crotta, Stefania, Gad, Hans Henrik, Hessel, Edith M, Beinke, Soren, Hartmann, Rune, and Wack, Andreas
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Influenza A virus ( IAV)-induced severe disease is characterized by infected lung epithelia, robust inflammatory responses and acute lung injury. Since type I interferon ( IFNαβ) and type III interferon ( IFNλ) are potent antiviral cytokines with immunomodulatory potential, we assessed their efficacy as IAV treatments. IFNλ treatment of IAV-infected Mx1-positive mice lowered viral load and protected from disease. IFNα treatment also restricted IAV replication but exacerbated disease. IFNα treatment increased pulmonary proinflammatory cytokine secretion, innate cell recruitment and epithelial cell death, unlike IFNλ-treatment. IFNλ lacked the direct stimulatory activity of IFNα on immune cells. In epithelia, both IFNs induced antiviral genes but no inflammatory cytokines. Similarly, human airway epithelia responded to both IFNα and IFNλ by induction of antiviral genes but not of cytokines, while hPBMCs responded only to IFNα. The restriction of both IFNλ responsiveness and productive IAV replication to pulmonary epithelia allows IFNλ to limit IAV spread through antiviral gene induction in relevant cells without overstimulating the immune system and driving immunopathology. We propose IFNλ as a non-inflammatory and hence superior treatment option for human IAV infection. [ABSTRACT FROM AUTHOR]
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- 2016
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25. Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling.
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Ibsen, Mikkel Søes, Gad, Hans Henrik, Andersen, Line Lykke, Hornung, Veit, Julkunen, Ilkka, Sarkar, Saumendra N., and Hartmann, Rune
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- 2015
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26. Rapid Uptake and Inhibition of Viral Propagation by Extracellular OAS1.
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Thavachelvam, Karthiga, Gad, Hans Henrik, Ibsen, Mikkel Søes, Desprès, Philippe, Hokland, Marianne, Hartmann, Rune, and Kristiansen, Helle
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OLIGOADENYLATE synthetase , *RIBONUCLEASE L , *HEPARIN , *VIRAL replication , *RECOMBINANT proteins - Abstract
The oligoadenylate synthetase (OAS) proteins are traditionally considered intracellular antiviral proteins that mediate antiviral activity through the synthesis of 2′-5′-linked oligoadenylates and subsequent activation of the endoribonuclease RNase L. However, we have recently demonstrated that exogenous recombinant OAS1 is taken up by cells and reduces viral replication both in cell culture and in vivo, independent of RNase L. These results demonstrate a novel paracrine antiviral activity of OAS working in parallel with the classical RNase L pathway. In this study, we investigate the uptake kinetics of recombinant porcine OAS1 and show that it is rapidly and efficiently internalized in a manner that can be blocked by heparin. Heparin, furthermore, abolishes the antiviral activity of OAS1, demonstrating the requirement of the intracellular localization of OAS1 to inhibit the virus. In addition, we demonstrate that exogenous OAS1 affects an early step of the viral replication cycle. [ABSTRACT FROM AUTHOR]
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- 2015
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27. The 2'-5'-Oligoadenylate Synthetase 3 Enzyme Potently Synthesizes the 2'-5'-Oligoadenylates Required for RNase L Activation.
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Ibsen, Mikkel Søes, Gad, Hans Henrik, Thavachelvam, Karthiga, Boesen, Thomas, Desprès, Philippe, and Hartmann, Rune
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OLIGOADENYLATE synthetase , *ENZYMES , *CHEMICAL synthesis , *RIBONUCLEASE L , *ANTIVIRAL agents , *RNA viruses , *DNA viruses - Abstract
The members of the oligoadenylate synthetase (OAS) family of proteins are antiviral restriction factors that target a wide range of RNA and DNA viruses. They function as intracellular double-stranded RNA (dsRNA) sensors that, upon binding to dsRNA, undergo a conformational change and are activated to synthesize 2'-5'-linked oligoadenylates (2-5As). 2-5As of sufficient length act as second messengers to activate RNase L and thereby restrict viral replication. We expressed human OAS3 using the baculovirus system and purified it to homogeneity. We show that recombinant OAS3 is activated at a substantially lower concentration of dsRNA than OAS1, making it a potent in vivo sensor of dsRNA. Moreover, we find that OAS3 synthesizes considerably longer 2-5As than previously reported, and that OAS3 can activate RNase L intracellularly. The combined high affinity for dsRNA and the capability to produce 2-5As of sufficient length to activate RNase L suggests that OAS3 is a potent activator of RNase L. In addition, we provide experimental evidence to support one active site of OAS3 located in the C-terminal OAS domain and generate a low-resolution structure of OAS3 using SAXS. [ABSTRACT FROM AUTHOR]
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- 2014
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28. 85 : A novel role for the oligoadenylate synthetase-like protein in viral recognition and interferon induction
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Gad, Hans Henrik, Ibsen, Mikkel S., Andersen, Line L., Hornung, Veit, Sarka, Saumendra N., and Hartmann, Rune
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- 2013
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29. Lambda Interferons: New Cytokines with Old Functions.
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Hamming, Ole J., Gad, Hans Henrik, Paludan, Søren, and Hartmann, Rune
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- 2010
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30. Interferon-λ Is Functionally an Interferon but Structurally Related to the Interleukin-10 Family.
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Gad, Hans Henrik, Dellgren, Christoffer, Hamming, Ole J., Vends, Susanne, Paludan, Søren R., and Hartmann, Rune
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INTERFERONS , *INTERLEUKIN-10 , *CYTOKINES , *MUTAGENESIS , *PHOSPHORYLATION , *BACTERIAL diseases - Abstract
Interferon-λ (IFN-λ) is an antiviral cytokine that signals through a distinct receptor complex, composed of the IFN-λR1 and interleukin10R2 (IL10R2) receptor chains. We have determined the crystal structure of human IFN-λ3 and characterized the interaction with its receptor complex through structurebased site-directed mutagenesis. The ability of IFN-A3 mutants to signal was determined by measuring the antiviral activity and induced STAT2 phosphor'ylation. In conclusion, our data show that, although IFN-λ is functionally an interferon, it is clearly structurally related to members of the IL-b family. In particular, we found an interesting similarity between IFN-λ and IL-22, and we suggest that IFN-λ and IL-22 possess parallel functions, protecting epithelial tissue against viral and bacterial infections, respectively. [ABSTRACT FROM AUTHOR]
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- 2009
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31. PS2-008. Mapping the active site and investigating the polyI:C inducibility of the human 120 kDa 2’-5’ Oligoadenylate Synthetase 3
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Ibsen, Mikkel, Gad, Hans Henrik, Despres, Philippe, and Hartmann, Rune
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- 2011
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32. SS10-7 The battle between host and virus: how chikungunya virus is inhibited by 2′-5′-oligoadenylate synthetases and how it may escape the battle
- Author
-
Gad, Hans Henrik, Paulous, Sylvie, Caro, Valerie, Hartmann, Rune, Kümmerer, Beate, and Despres, Philippe
- Published
- 2010
- Full Text
- View/download PDF
33. Inhibition of SARS-CoV-2 by type I and type III interferons.
- Author
-
Felgenhauer, Ulrike, Schoen, Andreas, Gad, Hans Henrik, Hartmann, Rune, Schaubmar, Andreas R., Failing, Klaus, Drosten, Christian, and Weber, Friedemann
- Subjects
- *
SARS-CoV-2 , *SARS disease , *TYPE I interferons , *COVID-19 - Abstract
The recently emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the devastating COVID-19 lung disease pandemic. Here, we tested the inhibitory activities of the antiviral interferons of type I (IFN-a) and type III (IFN-l) against SARS-CoV-2 and compared them with those against SARS-CoV-1, which emerged in 2003. Using two mammalian epithelial cell lines (human Calu-3 and simian Vero E6), we found that both IFNs dose-dependently inhibit SARS-CoV-2. In contrast, SARS-CoV-1 was restricted only by IFN-a in these cell lines. SARS-CoV-2 generally exhibited a broader IFN sensitivity than SARS-CoV-1. Moreover, ruxolitinib, an inhibitor of IFN-triggered Janus kinase/signal transducer and activator of transcription signaling, boosted SARS-CoV-2 replication in the IFN-competent Calu-3 cells. We conclude that SARS-CoV-2 is sensitive to exogenously added IFNs. This finding suggests that type I and especially the less adverse effect-prone type III IFN are good candidates for the management of COVID-19. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
34. Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses.
- Author
-
Holm, Christian K., Rahbek, Stine H., Gad, Hans Henrik, Bak, Rasmus O., Jakobsen, Martin R., Jiang, Zhaozaho, Hansen, Anne Louise, Jensen, Simon K., Sun, Chenglong, Thomsen, Martin K., Laustsen, Anders, Nielsen, Camilla G., Severinsen, Kasper, Xiong, Yingluo, Burdette, Dara L., Hornung, Veit, Lebbink, Robert Jan, Duch, Mogens, Fitzgerald, Katherine A., and Bahrami, Shervin
- Published
- 2016
- Full Text
- View/download PDF
35. ID: 191: Comparing the stability and activity of recombinant IFNλ3 and IFNλ4.
- Author
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Gad, Hans Henrik, Christensen, Kasper Thorhauge, Terczyńska-Dyla, Ewa, and Hartmann, Rune
- Subjects
- *
RECOMBINANT antibodies , *HEPATITIS C virus , *TYPE I interferons , *CYTOKINES , *GENOMES - Abstract
Hepatitis C virus (HCV) infection is one of the major causes of liver cancer worldwide and every year 3–4 million people become infected. Whereas some infected people eradicate the virus spontaneously, almost 85% do not and instead develop a chronic infection. Recently, it was shown that people with a functional IFNL4 gene have a lower chance of clearing the virus spontaneously or in response to treatment than people with a non-functional IFNL4 gene. Why it is a disadvantage to have a functional IFNL4 gene during HCV infection is currently not known although a causal relationship between the activity of the IFN λ 4 protein and poor HCV clearance has been demonstrated. IFN λ 4 belongs to the type III IFNs together with IFN λ 1, -2, and -3. However, it differs from the others not only by its low sequence similarity but also by its impaired secretion. This impairment is not due to a weak signal peptide, as swapping the signal peptides between IFN λ 3 and -4 had no effect on secretion. When we purified IFN λ 3 and -4, we found that IFN λ 4 is far more difficult to refold in vitro than IFN λ 3 suggesting that the poor secretion of IFN λ 4 could be due to an inherent problem of folding the protein. Because such a problem could also mean that IFN λ 4 could be far unstable than the other type III IFNs, we decided to compare the stability of recombinant IFN λ 3 and IFN λ 4. Our results demonstrate that IFN λ 4 like IFN λ 3 is surprisingly stable once it has folded properly. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
36. Effective Interferon Lambda Treatment Regimen To Control Lethal MERS-CoV Infection in Mice.
- Author
-
Dijkman, Ronald, Kumar Verma, Abhishek, Selvaraj, Muneeswaran, Ghimire, Roshan, Gad, Hans Henrik, Hartmann, Rune, More, Sunil, Perlman, Stanley, Thiel, Volker, and Channappanavar, Rudragouda
- Subjects
- *
EMERGING infectious diseases , *VIRUS diseases , *MICE , *ANTIVIRAL agents , *INTERFERON receptors , *MIDDLE East respiratory syndrome - Abstract
Effective broad-spectrum antivirals are critical to prevent and control emerging human coronavirus (hCoV) infections. Despite considerable progress made toward identifying and evaluating several synthetic broad-spectrum antivirals against hCoV infections, a narrow therapeutic window has limited their success. Enhancing the endogenous interferon (IFN) and IFN-stimulated gene (ISG) response is another antiviral strategy that has been known for decades. However, the side effects of pegylated type-I IFNs (IFN-Is) and the proinflammatory response detected after delayed IFN-I therapy have discouraged their clinical use. In contrast to IFN-Is, IFN-λ, a dominant IFN at the epithelial surface, has been shown to be less proinflammatory. Consequently, we evaluated the prophylactic and therapeutic efficacy of IFN-λ in hCoV-infected airway epithelial cells and mice. Human primary airway epithelial cells treated with a single dose of IFN-I (IFN- a) and IFN-λ showed similar ISG expression, whereas cells treated with two doses of IFN-λ expressed elevated levels of ISG compared to that of IFN- a-treated cells. Similarly, mice treated with two doses of IFN-λ were better protected than mice that received a single dose, and a combination of prophylactic and delayed therapeutic regimens completely protected mice from a lethal Middle East respiratory syndrome CoV (MERS-CoV) infection. A two-dose IFN-λ regimen significantly reduced lung viral titers and inflammatory cytokine levels with marked improvement in lung inflammation. Collectively, we identified an effective regimen for IFN-λ use and demonstrated the protective efficacy of IFN- l in MERS-CoV-infected mice. IMPORTANCE Effective antiviral agents are urgently required to prevent and treat individuals infected with SARS-CoV-2 and other emerging viral infections. The COVID-19 pandemic has catapulted our efforts to identify, develop, and evaluate several antiviral agents. However, a narrow therapeutic window has limited the protective efficacy of several broad-spectrum and CoV-specific antivirals. IFN-λ is an antiviral agent of interest due to its ability to induce a robust endogenous antiviral state and low levels of inflammation. Here, we evaluated the protective efficacy and effective treatment regimen of IFN-λ in mice infected with a lethal dose of MERS-CoV. We show that while prophylactic and early therapeutic IFN-λ administration is protective, delayed treatment is detrimental. Notably, a combination of prophylactic and delayed therapeutic administration of IFN-λ protected mice from severe MERS. Our results highlight the prophylactic and therapeutic use of IFN-λ against lethal hCoV and likely other viral lung infections. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
37. Length dependent activation of OAS proteins by dsRNA.
- Author
-
Wang, Yinbiao, Holleufer, Andreas, Gad, Hans Henrik, and Hartmann, Rune
- Subjects
- *
DOUBLE-stranded RNA , *BASE pairs , *PROTEINS , *VIRUS diseases , *MONOMERS - Abstract
The oligoadenylate synthetase (OAS) family of enzymes are interferon-inducible antiviral proteins, which synthesize the secondary messenger 2′-5′-linked oligoadenosine (2-5A) in response to viral infection. The production of 2-5As induces RNA decay within the infected cells, thereby effectively preventing further viral replication. OAS shares structural similarity as well as the enzymatic mechanism with a different antiviral protein, cyclic GMP-AMP synthase (cGAS), but OAS is activated by dsRNA whereas cGAS is activated by dsDNA. Here, we have studied the structural requirement for the dsRNA activating OAS1 and OAS3, and compared it to recent studies on cGAS. We find that both OAS1 and OAS3, like cGAS, achieve their maximum activity with dsRNA molecules that are substantial longer than what one monomer of the enzyme can interact with. One molecule of OAS1 can cover approximately 18–20 base pairs of dsRNA, which is just short of two turns of a helix. However, RNAs of this length gave a very limited activity and the length dependency was even more pronounced for OAS3. Our data suggest that the OAS enzymes evolved to recognize long dsRNA as virally derived PAMPs, and that the length of the dsRNA is an important factor in discriminating self from non-self. Several structures of OAS1 bound to short dsRNAs exist, but our data show that OAS can only achieve minimal activity with these short activators (approximately 7–8% of maximal activity) and it is thus possible that these structures do not reveal the fully activated state of the OAS enzymes. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
38. The IFNL4 1 gene is a non-canonical interferon gene with a unique but evolutionarily conserved regulation.
- Author
-
Hao Zhou, Møhlenberg, Michelle, Terczyńska-Dyla, Ewa, Winther, Kasper Grønbjerg, Hansen, Nanna Hougaard, Vad-Nielsen, Johan, Laloli, Laura, Dijkman, Ronald, Nielsen, Anders Lade, Gad, Hans Henrik, and Hartmann, Rune
- Subjects
- *
INTERFERON regulatory factors , *TRANSCRIPTION factors , *INTERFERON receptors , *GENETIC regulation , *BINDING sites , *VIRUS diseases - Abstract
Interferon lambda 4 (IFNL4) is a recently identified enigmatic member of the interferon lambda family. Genetic data suggest that the IFNL4 gene acts in a pro-viral and anti-inflammatory manner in patients. However, the protein is in vitro indistinguishable from the other members of the interferon lambda family. We have investigated the gene regulation of IFNL4 in detail and found that it differs radically from that of canonical antiviral interferons. Being induced by viral infection is a defining characteristic of interferons, but viral infection or overexpression of members of the interferon regulatory factor (IRF) family of transcription factors only leads to a minute induction of IFNL4. This behavior is evolutionarily conserved and can be reversed by inserting a functional IRF3 binding site into the IFNL4 promoter. Thus, the regulation of the IFNL4 gene is radically different and might explain some of the atypical phenotypes associated with the IFNL4 gene in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
39. Type I and Type III Interferons Differ in Their Adjuvant Activities for Influenza Vaccines.
- Author
-
Liang Ye, Ohnemus, Annette, Li Ching Ong, Gad, Hans Henrik, Hartmann, Rune, Lycke, Nils, and Staeheli, Peter
- Subjects
- *
INFLUENZA vaccines , *INTERFERON receptors , *THYMIC stromal lymphopoietin , *VACCINE effectiveness , *VIRUS diseases , *ANTIBODY formation , *NEURAMINIDASE , *TYPE I interferons - Abstract
Type I and type III interferons (IFNs) can promote adaptive immune responses in mice and improve vaccine-induced resistance to viral infections. The adjuvant effect of type III IFN (IFN-λ) specifically boosts mucosal immunity by an indirect mechanism, involving IFN-λ-induced production of thymic stromal lymphopoietin (TSLP), a cytokine that activates immune cells. To date, it remained unclear whether the previously described adjuvant effect of type I IFN (IFN-α/β) would also depend on TSLP and whether type I IFN stimulates different antibody subtypes. Here, we show that after infection with a live attenuated influenza virus, mice lacking functional type I IFN receptors failed to produce normal amounts of virus-specific IgG2c and IgA antibodies. In contrast, mice lacking functional IFN-λ receptors contained normal levels of virus-specific IgG2c but had reduced IgG1 and IgA antibody levels. When applied together with protein antigen, IFN-α stimulated the production of antigen-specific IgA and IgG2c to a greater extent than IgG1, irrespective of whether the mice expressed functional TSLP receptors and irrespective of whether the vaccine was applied by the intranasal or the intraperitoneal route. Taken together, these results demonstrate that the adjuvant activities of type I and type III IFNs are mechanistically distinct. IMPORTANCE Interferons can shape antiviral immune responses, but it is not well understood how they influence vaccine efficacy. We find that type I IFN preferentially promotes the production of antigen-specific IgG2c and IgA antibodies after infection with a live attenuated influenza virus or after immunization with influenza subunit vaccines. In contrast, type III IFN specifically enhances influenza virus-specific IgG1 and IgA production. The adjuvant effect of type I IFN was not dependent on TSLP, which is essential for the adjuvant effect of type III IFN. Type I IFN boosted vaccine-induced antibody production after immunization by the intranasal or the intraperitoneal route, whereas type III IFN exhibited its adjuvant activity only when the vaccine was delivered by the mucosal route. Our findings demonstrate that type I and type III IFNs trigger distinct pathways to enhance the efficacy of vaccines. This knowledge might be used to design more efficient vaccines against infectious diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
40. Mapping of Chikungunya Virus Interactions with Host Proteins Identified nsP2 as a Highly Connected Viral Component.
- Author
-
Bouraï, Mehdi, Lucas-Hourani, Marianne, Gad, Hans Henrik, Drosten, Christian, Jacob, Yves, Tafforeau, Lionel, Cassonnet, Patricia, Jones, Louis M., Judith, Delphine, Couderc, Thé(c)rèse, Lecuit, Marc, André(c), Patrice, Ké1/4mmerer, Beate Mareike, Lotteau, Vincent, Desprès, Philippe, Tangy, Fré(c)dé(c)ric, and Vidalain, Pierre-Olivier
- Subjects
- *
CHIKUNGUNYA , *GENE mapping , *EPIDEMICS , *ALPHAVIRUS diseases , *MOSQUITO vectors , *VIRAL proteins , *GENE silencing , *VIRAL replication - Abstract
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has been responsible for an epidemic outbreak of unprecedented magnitude in recent years. Since then, significant efforts have been made to better understand the biology of this virus, but we still have poor knowledge of CHIKV interactions with host cell components at the molecular level. Here we describe the extensive use of high-throughput yeast two-hybrid (HT-Y2H) assays to characterize interactions between CHIKV and human proteins. A total of 22 high-confidence interactions, which essentially involved the viral nonstructural protein nsP2, were identified and further validated in protein complementation assay (PCA). These results were integrated to a larger network obtained by extensive mining of the literature for reports on alphavirus-host interactions. To investigate the role of cellular proteins interacting with nsP2, gene silencing experiments were performed in cells infected by a recombinant CHIKV expressing Renilla luciferase as a reporter. Collected data showed that heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and ubiquilin 4 (UBQLN4) participate in CHIKV replication in vitro. In addition, we showed that CHIKV nsP2 induces a cellular shutoff, as previously reported for other Old World alphaviruses, and determined that among binding partners identified by yeast two-hybrid methods, the tetratricopeptide repeat protein 7B (TTC7B) plays a significant role in this activity. Altogether, this report provides the first interaction map between CHIKV and human proteins and describes new host cell proteins involved in the replication cycle of this virus. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
41. ID: 101: Investigating the role of interferon λ4 in hepatitis C virus infection.
- Author
-
Terczynska-Dyla, Ewa, Bibert, Stephanie, Duong, Francois H.T., Lauber, Chris, Gad, Hans Henrik, Kaderali, Lars, Heim, Markus H., Bochud, Pierre-Yves, and Hartmann, Rune
- Subjects
- *
INTERFERONS , *HEPATITIS C virus , *CYTOKINES , *GENOMES , *MEDICAL microbiology - Abstract
IFNL4 , a recently discovered member of the interferon λ family (IFN λ s or type III IFNs), is a pseudogene in a significant fraction of the human population. A single nucleotide polymorphism located in IFNL4 , which determines the ability to express IFN λ 4, has been correlated with poor spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infections. We show that IFN λ 4 is an active type III IFN that induces a typical subset of ISGs, signals through the classical type III IFN receptor complex and is antiviral against HCV and coronaviruses. However, its secretion is impaired and this impairment is caused by a yet unknown molecular determinant, but appears to be partially caused by a weak signal peptide and inefficient N-linked glycosylation. This glycosylation is not required for antiviral activity and secretion of IFN λ 4, but seems to improve its processing. The impaired secretion of IFN λ 4 appears to be a recently acquired feature of primates. A single amino acid substitution in IFN λ 4 changing a proline at position 70 to a serine (P70S) alters its activity. We demonstrate that the IFN λ 4-S70 variant has a significantly lower antiviral activity compared to IFN λ 4-P70. Our subsequent genetic study on a cohort of patients infected with HCV shows that individuals, who encode IFN λ 4-S70, display lower hepatic ISG expression, better treatment response rates and better spontaneous clearance rates than patients encoding IFN λ 4-P70. This study provides important evidence supporting a role for active IFN λ 4 as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
42. The IFNL4 Gene Is a Noncanonical Interferon Gene with a Unique but Evolutionarily Conserved Regulation.
- Author
-
Zhou H, Møhlenberg M, Terczyńska-Dyla E, Winther KG, Hansen NH, Vad-Nielsen J, Laloli L, Dijkman R, Nielsen AL, Gad HH, and Hartmann R
- Subjects
- A549 Cells, Animals, Antiviral Agents pharmacology, Base Sequence, Gene Expression Regulation, HEK293 Cells, Hep G2 Cells, Hepacivirus physiology, Hepatitis C metabolism, Humans, Inflammation, Interferons classification, Interleukins classification, Interleukins genetics, Interleukins pharmacology, Liver pathology, RNA, Messenger metabolism, Sequence Alignment, THP-1 Cells, Evolution, Molecular, Interferons genetics, Interferons metabolism
- Abstract
Interferon lambda 4 (IFN-λ4) is a recently identified enigmatic member of the interferon (IFN) lambda family. Genetic data suggest that the IFNL4 gene acts in a proviral and anti-inflammatory manner in patients. However, the protein is indistinguishable in vitro from the other members of the interferon lambda family. We have investigated the gene regulation of IFNL4 in detail and found that it differs radically from that of canonical antiviral interferons. Being induced by viral infection is a defining characteristic of interferons, but viral infection or overexpression of members of the interferon regulatory factor (IRF) family of transcription factors only leads to a minute induction of IFNL4 This behavior is evolutionarily conserved and can be reversed by inserting a functional IRF3 binding site into the IFNL4 promoter. Thus, the regulation of the IFNL4 gene is radically different and might explain some of the atypical phenotypes associated with the IFNL4 gene in humans. IMPORTANCE Recent genetic evidence has highlighted how the IFNL4 gene acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. This suggests that the IFNL4 gene acts in a proviral and anti-inflammatory manner. These surprising but quite clear genetic data have prompted an extensive examination of the basic characteristics of the IFNL4 gene and its gene product, interferon lambda 4 (IFN-λ4). We have investigated the expression of the IFNL4 gene and found it to be poorly induced by viral infections. A thorough investigation of the IFNL4 promoter revealed a highly conserved and functional promoter, but also one that lacks the defining characteristic of interferons (IFNs), i.e., the ability to be effectively induced by viral infections. We suggest that the unique function of the IFNL4 gene is related to its noncanonical transcriptional regulation., (Copyright © 2020 American Society for Microbiology.)
- Published
- 2020
- Full Text
- View/download PDF
43. Type I and Type III Interferons Differ in Their Adjuvant Activities for Influenza Vaccines.
- Author
-
Ye L, Ohnemus A, Ong LC, Gad HH, Hartmann R, Lycke N, and Staeheli P
- Subjects
- Animals, Antibody Formation immunology, Cytokines, Disease Models, Animal, Female, Immunity, Mucosal immunology, Immunization, Immunoglobulin A immunology, Immunoglobulin G immunology, Immunoglobulins genetics, Interferon Type I, Interferons genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Orthomyxoviridae Infections virology, Receptors, Cytokine genetics, Vaccination, Interferon Lambda, Thymic Stromal Lymphopoietin, Adaptive Immunity immunology, Adjuvants, Immunologic, Influenza Vaccines immunology, Interferons immunology
- Abstract
Type I and type III interferons (IFNs) can promote adaptive immune responses in mice and improve vaccine-induced resistance to viral infections. The adjuvant effect of type III IFN (IFN-λ) specifically boosts mucosal immunity by an indirect mechanism, involving IFN-λ-induced production of thymic stromal lymphopoietin (TSLP), a cytokine that activates immune cells. To date, it remained unclear whether the previously described adjuvant effect of type I IFN (IFN-α/β) would also depend on TSLP and whether type I IFN stimulates different antibody subtypes. Here, we show that after infection with a live attenuated influenza virus, mice lacking functional type I IFN receptors failed to produce normal amounts of virus-specific IgG2c and IgA antibodies. In contrast, mice lacking functional IFN-λ receptors contained normal levels of virus-specific IgG2c but had reduced IgG1 and IgA antibody levels. When applied together with protein antigen, IFN-α stimulated the production of antigen-specific IgA and IgG2c to a greater extent than IgG1, irrespective of whether the mice expressed functional TSLP receptors and irrespective of whether the vaccine was applied by the intranasal or the intraperitoneal route. Taken together, these results demonstrate that the adjuvant activities of type I and type III IFNs are mechanistically distinct. IMPORTANCE Interferons can shape antiviral immune responses, but it is not well understood how they influence vaccine efficacy. We find that type I IFN preferentially promotes the production of antigen-specific IgG2c and IgA antibodies after infection with a live attenuated influenza virus or after immunization with influenza subunit vaccines. In contrast, type III IFN specifically enhances influenza virus-specific IgG1 and IgA production. The adjuvant effect of type I IFN was not dependent on TSLP, which is essential for the adjuvant effect of type III IFN. Type I IFN boosted vaccine-induced antibody production after immunization by the intranasal or the intraperitoneal route, whereas type III IFN exhibited its adjuvant activity only when the vaccine was delivered by the mucosal route. Our findings demonstrate that type I and type III IFNs trigger distinct pathways to enhance the efficacy of vaccines. This knowledge might be used to design more efficient vaccines against infectious diseases., (Copyright © 2019 American Society for Microbiology.)
- Published
- 2019
- Full Text
- View/download PDF
44. IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission.
- Author
-
Klinkhammer J, Schnepf D, Ye L, Schwaderlapp M, Gad HH, Hartmann R, Garcin D, Mahlakõiv T, and Staeheli P
- Subjects
- Animals, Cytokines metabolism, Lung immunology, Lung virology, Mice, Mice, Inbred C57BL, Mice, Knockout, Orthomyxoviridae Infections transmission, Orthomyxoviridae Infections virology, Respiratory System immunology, Respiratory System virology, Virus Replication, Antiviral Agents pharmacology, Interferon-gamma pharmacology, Lung drug effects, Orthomyxoviridae drug effects, Orthomyxoviridae Infections prevention & control, Receptors, Interferon physiology, Respiratory System drug effects
- Abstract
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., Competing Interests: JK, DS, LY, MS, HG, RH, DG, TM, PS No competing interests declared, (© 2018, Klinkhammer et al.)- Published
- 2018
- Full Text
- View/download PDF
45. Functional IRF3 deficiency in a patient with herpes simplex encephalitis.
- Author
-
Andersen LL, Mørk N, Reinert LS, Kofod-Olsen E, Narita R, Jørgensen SE, Skipper KA, Höning K, Gad HH, Østergaard L, Ørntoft TF, Hornung V, Paludan SR, Mikkelsen JG, Fujita T, Christiansen M, Hartmann R, and Mogensen TH
- Subjects
- Adolescent, Amino Acid Substitution, Encephalitis, Herpes Simplex metabolism, Encephalitis, Herpes Simplex pathology, Female, Fibroblasts pathology, Fibroblasts virology, Herpesvirus 1, Human genetics, Humans, Interferon Regulatory Factor-3 metabolism, Interferon Type I biosynthesis, Interferon Type I genetics, Phosphorylation, Protein Multimerization genetics, Encephalitis, Herpes Simplex genetics, Fibroblasts metabolism, Haploinsufficiency, Herpesvirus 1, Human metabolism, Interferon Regulatory Factor-3 deficiency, Mutation, Missense
- Abstract
Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon (IFN) production downstream of Toll-like receptor 3. Here, we describe a novel genetic etiology of HSE by identifying a heterozygous loss-of-function mutation in the IFN regulatory factor 3 (IRF3) gene, leading to autosomal dominant (AD) IRF3 deficiency by haploinsufficiency, in an adolescent female patient with HSE. IRF3 is activated by most pattern recognition receptors recognizing viral infections and plays an essential role in induction of type I IFN. The identified IRF3 R285Q amino acid substitution results in impaired IFN responses to HSV-1 infection and particularly impairs signaling through the TLR3-TRIF pathway. In addition, the R285Q mutant of IRF3 fails to become phosphorylated at S386 and undergo dimerization, and thus has impaired ability to activate transcription. Finally, transduction with WT IRF3 rescues the ability of patient fibroblasts to express IFN in response to HSV-1 infection. The identification of IRF3 deficiency in HSE provides the first description of a defect in an IFN-regulating transcription factor conferring increased susceptibility to a viral infection in the CNS in humans., (© 2015 Andersen et al.)
- Published
- 2015
- Full Text
- View/download PDF
46. The oligoadenylate synthetase family: an ancient protein family with multiple antiviral activities.
- Author
-
Kristiansen H, Gad HH, Eskildsen-Larsen S, Despres P, and Hartmann R
- Subjects
- 2',5'-Oligoadenylate Synthetase chemistry, 2',5'-Oligoadenylate Synthetase genetics, Animals, Endoribonucleases chemistry, Endoribonucleases metabolism, Enzyme Activation, Host-Pathogen Interactions, Humans, Protein Conformation, RNA Stability, RNA, Double-Stranded metabolism, RNA, Viral metabolism, 2',5'-Oligoadenylate Synthetase metabolism, Gene Expression Regulation, Enzymologic, Interferons metabolism, Virus Diseases metabolism, Virus Inactivation
- Abstract
The 2'-5' oligoadenylate synthetases (OAS) are interferon-induced antiviral enzymes that recognize virally produced dsRNA and initiate RNA destabilization through activation of RNase L within infected cells. However, recent evidence points toward several RNase L-independent pathways, through which members of the OAS family can exert antiviral activity. The crystal structure of OAS led to a novel insight into the catalytic mechanism, and revealed a remarkable similarity between OAS, Polyadenosine polymerase, and the class I CCA-adding enzyme from Archeoglobus fulgidus. This, combined with a variety of bioinformatic data, leads to the definition of a superfamily of template independent polymerases and proved that the OAS family are ancient proteins, which probably arose as early as the beginning of metazoan evolution.
- Published
- 2011
- Full Text
- View/download PDF
47. The structure of human interferon lambda and what it has taught us.
- Author
-
Gad HH, Hamming OJ, and Hartmann R
- Subjects
- Crystallization, Humans, Interferons, Interleukin-10 chemistry, Interleukin-10 immunology, Interleukin-10 metabolism, Interleukins chemistry, Interleukins immunology, Molecular Conformation, Protein Isoforms chemistry, Protein Isoforms immunology, Receptors, Cytokine immunology, Signal Transduction immunology, Structure-Activity Relationship, Interleukins metabolism, Protein Isoforms metabolism, Structural Homology, Protein
- Abstract
Type III interferon (IFN) or IFN-lambda is a novel family of class II cytokines that induces antiviral activities both in vitro and in vivo through its own distinctive receptor complex. The recent crystal structure of human IFN-lambda3 revealed a cytokine with structural similarity to the interleukin-10 family, despite functionally being an IFN. Here, we review the structure of IFN-lambda and its relation to the other members of the class II cytokines. Further, we analyze the structural differences between the tree human isoforms of IFN-lambda and relate this to the observed differences in potency.
- Published
- 2010
- Full Text
- View/download PDF
48. Selection of a novel and highly specific tumor necrosis factor alpha (TNFalpha) antagonist: insight from the crystal structure of the antagonist-TNFalpha complex.
- Author
-
Byla P, Andersen MH, Holtet TL, Jacobsen H, Munch M, Gad HH, Thøgersen HC, and Hartmann R
- Subjects
- Amino Acid Sequence, Animals, Apoptosis drug effects, Cell Line, Crystallography, X-Ray, Humans, In Vitro Techniques, Lectins, C-Type chemistry, Lectins, C-Type genetics, Mice, Models, Molecular, Molecular Sequence Data, Multiprotein Complexes, Peptide Library, Protein Structure, Quaternary, Protein Structure, Tertiary, Recombinant Proteins antagonists & inhibitors, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins pharmacology, Surface Plasmon Resonance, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha chemistry
- Abstract
Inhibition of tumor necrosis factor alpha (TNFalpha) is a favorable way of treating several important diseases such as rheumatoid arthritis, Crohn disease, and psoriasis. Therefore, an extensive range of TNFalpha inhibitory proteins, most of them based upon an antibody scaffold, has been developed and used with variable success as therapeutics. We have developed a novel technology platform using C-type lectins as a vehicle for the creation of novel trimeric therapeutic proteins with increased avidity and unique properties as compared with current protein therapeutics. We chose human TNFalpha as a test target to validate this new technology because of the extensive experience available with protein-based TNFalpha antagonists. Here, we present a novel and highly specific TNFalpha antagonist developed using this technology. Furthermore, we have solved the three-dimensional structure of the antagonist-TNFalpha complex by x-ray crystallography, and this structure is presented here. The structure has given us a unique insight into how the selection procedure works at a molecular level. Surprisingly little change is observed in the C-type lectin-like domain structure outside of the randomized regions, whereas a substantial change is observed within the randomized loops. Thus, the overall integrity of the C-type lectin-like domain is maintained, whereas specificity and binding affinity are changed by the introduction of a number of specific contacts with TNFalpha.
- Published
- 2010
- Full Text
- View/download PDF
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