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4 results on '"MESH: Interferon Regulatory Factor-3"'

1. HEXIM1 and NEAT1 Long Non-coding RNA Form a Multi-subunit Complex that Regulates DNA-Mediated Innate Immune Response

Author

Yamina Bennasser, Monsef Benkirane, Sonia Amraoui, Mehdi Morchikh, Julien Cau, Dany Severac, Olivier Schwartz, Alexandra Cribier, Raoul Raffel, Emeric Dubois, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the ANRS, European FP7 'HIT HIDDEN HIV' contract 305762 and MSDavenir. M.M. was supported by European FP7 'HIT HIDDEN HIV' contract 305762 and by foundation Bettencourt Schueller and A.C. was supported by SIDACTION., European Project: 305762,HEALTH,FP7-HEALTH-2012-INNOVATION-1,HIT HIDDEN HIV(2012), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, MESH: Signal Transduction, Ku80, [SDV]Life Sciences [q-bio], paraspeckles, RNA-binding protein, MESH: Calcium-Binding Proteins, HEXIM1, MESH: Interferon Regulatory Factor-3, Nuclear Matrix-Associated Proteins, RNA interference, MESH: Nucleotidyltransferases, MESH: Ku Autoantigen, MESH: Human Umbilical Vein Endothelial Cells, Genetics, Ku70, Intracellular Signaling Peptides and Proteins, MESH: DNA, Nuclear Proteins, RNA-Binding Proteins, Nucleotidyltransferases, 3. Good health, Cell biology, DNA-Binding Proteins, MESH: RNA, Long Noncoding, MESH: HEK293 Cells, Herpesvirus 8, Human, Host-Pathogen Interactions, Octamer Transcription Factors, RNA Interference, RNA, Long Noncoding, MESH: Immunity, Innate, MESH: Octamer Transcription Factors, MESH: Membrane Proteins, Protein Binding, Signal Transduction, interferon stimulatory DNA, MESH: RNA Interference, NEAT1, MESH: PTB-Associated Splicing Factor, Biology, Transfection, DNA-PK, 03 medical and health sciences, herpesvirus, MESH: Intracellular Signaling Peptides and Proteins, Human Umbilical Vein Endothelial Cells, Humans, MESH: Protein Binding, PTB-Associated Splicing Factor, Molecular Biology, Ku Autoantigen, MESH: Herpesvirus 8, Human, [SDV.GEN]Life Sciences [q-bio]/Genetics, Innate immune system, MESH: Humans, MESH: Transfection, Calcium-Binding Proteins, MESH: Host-Pathogen Interactions, RNA, Membrane Proteins, Paraspeckle, Cell Biology, DNA, MESH: Multiprotein Complexes, Immunity, Innate, MESH: Nuclear Matrix-Associated Proteins, 030104 developmental biology, HEK293 Cells, MESH: RNA-Binding Proteins, Multiprotein Complexes, MESH: HeLa Cells, innate immune response, Interferon Regulatory Factor-3, IRF3, MESH: Nuclear Proteins, HeLa Cells, Transcription Factors, cGAS
Abstract

International audience; The DNA-mediated innate immune response underpins anti-microbial defenses and certain autoimmune diseases. Here we used immunoprecipitation, mass spectrometry, and RNA sequencing to identify a ribonuclear complex built around HEXIM1 and the long non-coding RNA NEAT1 that we dubbed the HEXIM1-DNA-PK-paraspeckle components-ribonucleoprotein complex (HDP-RNP). The HDP-RNP contains DNA-PK subunits (DNAPKc, Ku70, and Ku80) and paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATRIN3). We show that binding of HEXIM1 to NEAT1 is required for its assembly. We further demonstrate that the HDP-RNP is required for the innate immune response to foreign DNA, through the cGAS-STING-IRF3 pathway. The HDP-RNP interacts with cGAS and its partner PQBP1, and their interaction is remodeled by foreign DNA. Remodeling leads to the release of paraspeckle proteins, recruitment of STING, and activation of DNAPKc and IRF3. Our study establishes the HDP-RNP as a key nuclear regulator of DNA-mediated activation of innate immune response through the cGAS-STING pathway.

Published
2017
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2. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

Author

Majounie, E1, Renton, Ae, Mok, K, Dopper, Eg, Waite, A, Rollinson, S, Chiò, A, Restagno, G, Nicolaou, N, Simon-Sanchez, J, van Swieten JC, Abramzon, Y, Johnson, Jo, Sendtner, M, Pamphlett, R, Orrell, Rw, Mead, S, Sidle, Kc, Houlden, H, Rohrer, Jd, Morrison, Ke, Pall, H, Talbot, K, Ansorge, O, Hernandez, Dg, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Floris, Gl, Remes, Am, Laaksovirta, H, Mccluskey, L, Trojanowski, Jq, Van Deerlin VM, Schellenberg, Gd, Nalls, Ma, Drory, Ve, Lu, Cs, Yeh, Th, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, Pj, Heutink, P, Morris, Hr, Pickering-Brown, S, Traynor, Bj, Adamson, G, Bayer, Aj, Beck, J, Callister, Jb, Blake, Dj, Blumen, Sc, Collinge, J, Dunckley, T, Ealing, J, East, S, Elman, L, Gerhard, A, Guerreiro, Rj, Gwinn, K, Halliwell, N, Hamdalla, Hh, Hewitt, C, Ince, P, Jablonka, S, James, C, Kent, L, Knock, Jc, Lynch, T, Mahoney, C, Mann, D, Neal, J, Norris, D, O'Dowd, S, Richardson, A, Rossor, M, Rothstein, J, Scholz, Sw, Snowden, J, Stephan, Da, Toulson, G, Turner, Mr, Warren, Jd, Young, K, Weng, Yh, Kuo, Hc, Lai, Sc, Huang, Cl, Camuzat, A, Entraingues, L, Guillot-Noël, Verpillat, P, Blanc, F, Camu, W, Clerget-Darpoux, F, Corcia, P, Couratier, P, Didic, M, Dubois, B, Duyckaerts, C, Guedj, E, Golfier, V, Habert, Mo, Hannequin, D, Lacomblez, L, Meininger, V, Salachas, F, Levy, R, Michel, Bf, Pasquier, F, Puel, M, Thomas-Anterion, C, Sellal, F, Vercelletto, M, Moglia, C, Cammarosano, S, Canosa, A, Gallo, S, Brunetti, M, Ossola, I, Marinou, K, Papetti, L, Pisano, F, Pinter, Gl, Conte, A, Luigetti, M, Zollino, M, Lattante, S, Marangi, G, la Bella, V, Spataro, R, Colletti, T, Battistini, S, Ricci, C, Caponnetto, C, Mancardi, G, Mandich, P, Salvi, F, Bartolomei, I, Mandrioli, J, Sola, P, Lunetta, C, Penco, S, Monsurrò, Mr, Tedeschi, G, Conforti, Fl, Gambardella, A, Quattrone, A, Volanti, P, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, Mg, Murru, Mr, Pugliatti, M, Parish, Ld, Sotgiu, A, Solinas, G, Ulgheri, L, Ticca, A, Simone, I, Logroscino, G., Neurology, Erasmus MC other, The Chromosome 9-ALS/FTD Consortium, Human genetics, NCA - Neurodegeneration, Università degli studi di Torino (UNITO), Department of Clinical Genetics, Institute for Clinical Neurobiology, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), MRC Prion Unit, UCL Institute of neurology, UCL Institute of Neurology, UCL Institute of Neurology, Queen Square, London, Department of Neuroscience, Catholic University, Roma, Fondazione Maugeri, Department of Neuroscience, University of Siena, Siena, Department of Neurology, Chang Gung Memorial Hospital [Taipei] (CGMH), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Università degli studi di Torino = University of Turin (UNITO), Julius-Maximilians-Universität Würzburg (JMU), UCL Institute of Neurology, Queen Square [London], Università degli Studi di Siena = University of Siena (UNISI), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
MESH: Signal Transduction, Male, MESH: Vesicular Transport Proteins, MESH: Membrane Glycoproteins, MESH: DNA Repeat Expansion, MESH: Genotype, Cohort Studies, MESH: Protein Structure, Tertiary, MESH: Aged, 80 and over, MESH: Interferon Regulatory Factor-3, 0302 clinical medicine, C9orf72, MESH: Child, MESH: RNA, Small Interfering, 80 and over, genetics, Age of Onset, Child, MESH: Cohort Studies, MESH: Amyotrophic Lateral Sclerosis, MESH: Aged, Genetics, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, DNA Repeat Expansion, MESH: Toll-Like Receptor 4, Middle Aged, Penetrance, 3. Good health, Settore MED/26 - NEUROLOGIA, Neurology, MESH: Young Adult, MESH: HEK293 Cells, Child, Preschool, Frontotemporal Dementia, Female, Sample collection, Chromosomes, Human, Pair 9, MESH: Myeloid Differentiation Factor 88, Frontotemporal dementia, Human, Pair 9, Adult, MESH: Protein Transport, medicine.medical_specialty, Adolescent, Genotype, MESH: Age of Onset, MESH: RNA Interference, Clinical Neurology, MESH: Frontotemporal Dementia, MESH: Genetic Loci, TARDBP, Chromosomes, 03 medical and health sciences, Open Reading Frames, Young Adult, MESH: Cross-Sectional Studies, Internal medicine, medicine, MESH: Chemokine CCL5, Humans, ddc:610, Preschool, MESH: Adaptor Proteins, Signal Transducing, 030304 developmental biology, Aged, MESH: Adolescent, MESH: Humans, business.industry, MESH: Transfection, MESH: Child, Preschool, Haplotype, Amyotrophic Lateral Sclerosis, MESH: Adult, MESH: Adaptor Proteins, Vesicular Transport, MESH: Open Reading Frames, medicine.disease, MESH: Male, MESH: Cell Line, C9orf72 Protein, Cross-Sectional Studies, MESH: Endosomes, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), MESH: Lipopolysaccharides, MESH: Chromosomes, Human, Pair 9, business, Trinucleotide repeat expansion, MESH: Female, Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, genetics, Child, Child, Preschool, Chromosomes, genetics, Cohort Studies, Cross-Sectional Studies, DNA Repeat Expansion, genetics, Female, Frontotemporal Dementia, genetics, Genetic Loci, Genotype, Humans, Male, Middle Aged, Open Reading Frames, genetics, Young Adult, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS: In patients with sporadic ALS, we identified the repeat expansion in 236 (7*0%) of 3377 white individuals from the USA, Europe, and Australia, two (4*1%) of 49 black individuals from the USA, and six (8*3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39*3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6*0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24*8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. INTERPRETATION: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Published
2012
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3. Type I interferon induction is detrimental during infection with the Whipple's disease bacterium, Tropheryma whipplei

Author

Lena Alexopoulou, Jean-Louis Mege, Khatoun Al Moussawi, Eric Ghigo, Ulrich Kalinke, Benoit Desnues, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Paul-Ehrlich-Institut (PEI), Federal Institute for Vaccines and Biomedicines, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Haon, Marie Laure, and Université de la Méditerranée, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6236, Marseille, France.

Subjects
MESH: Signal Transduction, MESH: Interferon Type I, Fluorescent Antibody Technique, Gene Expression, Microbiology/Innate Immunity, Apoptosis, MESH: Mice, Knockout, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Mice, 0302 clinical medicine, MESH: Interferon Regulatory Factor-3, Interferon, MESH: Reverse Transcriptase Polymerase Chain Reaction, Macrophage, MESH: Animals, Whipple's disease, Phosphorylation, MESH: In Situ Nick-End Labeling, MESH: Whipple Disease, MESH: Fluorescent Antibody Technique, lcsh:QH301-705.5, Oligonucleotide Array Sequence Analysis, Mice, Knockout, 0303 health sciences, biology, Reverse Transcriptase Polymerase Chain Reaction, MESH: Enzyme-Linked Immunosorbent Assay, MESH: Macrophage Activation, M2 Macrophage, MESH: Tropheryma, 3. Good health, STAT1 Transcription Factor, Interferon Type I, Microbiology/Cellular Microbiology and Pathogenesis, Whipple Disease, medicine.drug, Research Article, Signal Transduction, lcsh:Immunologic diseases. Allergy, MAPK signaling cascades, MESH: Gene Expression, Immunology, DNA transcription, Blotting, Western, Macrophage polarization, Tropheryma, Enzyme-Linked Immunosorbent Assay, Transfection, Microbiology, Proinflammatory cytokine, Tropheryma whipplei, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Mice, Inbred C57BL, Virology, Immunology/Immunity to Infections, Genetics, medicine, Transcription factors, In Situ Nick-End Labeling, MESH: Blotting, Western, Animals, Molecular Biology, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, MESH: Mice, 030304 developmental biology, MESH: Apoptosis, MESH: Transfection, Gene Expression Profiling, Macrophages, MESH: Macrophages, Macrophage Activation, medicine.disease, biology.organism_classification, Mice, Inbred C57BL, lcsh:Biology (General), Immunology/Leukocyte Activation, MESH: Oligonucleotide Array Sequence Analysis, Parasitology, Interferon Regulatory Factor-3, Interferons, MESH: STAT1 Transcription Factor, IRF3, lcsh:RC581-607, 030215 immunology
Abstract

Macrophages are the first line of defense against pathogens. Upon infection macrophages usually produce high levels of proinflammatory mediators. However, macrophages can undergo an alternate polarization leading to a permissive state. In assessing global macrophage responses to the bacterial agent of Whipple's disease, Tropheryma whipplei, we found that T. whipplei induced M2 macrophage polarization which was compatible with bacterial replication. Surprisingly, this M2 polarization of infected macrophages was associated with apoptosis induction and a functional type I interferon (IFN) response, through IRF3 activation and STAT1 phosphorylation. Using macrophages from mice deficient for the type I IFN receptor, we found that this type I IFN response was required for T. whipplei-induced macrophage apoptosis in a JNK-dependent manner and was associated with the intracellular replication of T. whipplei independently of JNK. This study underscores the role of macrophage polarization in host responses and highlights the detrimental role of type I IFN during T. whipplei infection., Author Summary Innate immune cells are sentinels allowing the host to sense invading pathogens. Among them, macrophages are highly microbicidal and are able to kill microorganisms. However, several pathogens have evolved strategies to hijack macrophage responses in order to survive or replicate. Tropheryma whipplei is the agent of Whipple's disease, a systemic disease that associates arthropathy, weight loss and gastrointestinal symptoms. It has been known for several years that this bacterium has a tropism for macrophages, in which it replicates. In this study, we have shown that T. whipplei induces host cell apoptosis and a surprising macrophage activation, characterized by anti-inflammatory molecules and type I interferon (IFN) signaling, which is generally associated to viral infections. We demonstrate that this type I IFN response is critical for bacterial pathogenicity, as it is required for bacterial replication and provides the first step of the apoptotic program of infected macrophages. By identifying these signaling events induced in macrophage by T. whipplei, we can now better understand the molecular basis of the pathophysiology of Whipple's disease, of interest for clinical and therapeutic ends.

Published
2010
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4. Cell-cell fusion induced by measles virus amplifies the type I interferon response

Author

Johan Druelle, Timothy Fabian Wild, Florence Herschke, Denis Gerlier, Sébastien Plumet, Chantal Rabourdin-Combe, David Laine, Hélène Valentin, Olga Azocar, Thomas Duhen, Virologie et Pathologie Humaine (VirPath), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie fondamentale et clinique, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), BioSciences Lyon-Gerland (BLG), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported in part by grants from ANR (DG, ANR-MIME), INSERM, INCA-Canceropole 2004-2005 and ARC 3637. D.L., F.H., J.D., T.D., and S.P. were supported by a fellowship from MENRT, ARC and DGA, respectively., Measles and Interferon response, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie et Pathologie Humaine ( VirPath ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale ( INSERM ), BioSciences Lyon-Gerland ( BLG ), École normale supérieure - Lyon ( ENS Lyon ) -Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Hospices Civils de Lyon ( HCL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), École normale supérieure - Lyon ( ENS Lyon ) -IFR128-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Gerlier, Denis

Subjects
MESH : Cell Line, MESH: Interferon Type I, fusion, Interferon Regulatory Factor-7, MESH : Viral Fusion Proteins, Cellular Response to Infection, Giant Cells, MESH: Interferon Regulatory Factor-7, MESH : Virology, Cell Fusion, MESH: Giant Cells, MESH : Interferon Regulatory Factor-7, MESH: Interferon Regulatory Factor-3, Interferon, Chlorocebus aethiops, MESH : Interferon Regulatory Factor-3, MESH : Innate immunity, MESH: Animals, MESH : Viral Proteins, Mononegavirales, OCIS 000.1430, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH : Cell Nucleus, Cell fusion, Microscopy, Video, biology, MESH: Dendritic Cells, MESH : Microscopy, Video, interferon, MESH: Innate immunity, MESH : Epithelial Cells, MESH: Epithelial Cells, Interferon Type I, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Viral Fusion Proteins, medicine.drug, MESH: Cell Nucleus, Immunology, Microbiology, [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Virus, Cell Line, Measles virus, Viral Proteins, MESH : Interferon Type I, Virology, medicine, Animals, Humans, dendritic cells, MESH: Immunology, Cell Nucleus, MESH: Humans, MESH : Cell Fusion, MESH : Humans, MESH : Giant Cells, biology.organism_classification, Molecular biology, MESH: Viral Proteins, MESH: Cercopithecus aethiops, epithelial cells, MESH: Cell Line, MESH: Microscopy, Video, Giant cell, Cell culture, Insect Science, MESH : Dendritic Cells, measles virus, MESH: Cell Fusion, MESH : Immunology, MESH : Measles virus, Interferon Regulatory Factor-3, MESH : Animals, MESH : Cercopithecus aethiops, Viral Fusion Proteins, MESH: Measles virus, Interferon type I, MESH: Virology
Abstract

Measles virus (MeV) infection is characterized by the formation of multinuclear giant cells (MGC). We report that beta interferon (IFN-β) production is amplified in vitro by the formation of virus-induced MGC derived from human epithelial cells or mature conventional dendritic cells. Both fusion and IFN-β response amplification were inhibited in a dose-dependent way by a fusion-inhibitory peptide after MeV infection of epithelial cells. This effect was observed at both low and high multiplicities of infection. While in the absence of virus replication, the cell-cell fusion mediated by MeV H/F glycoproteins did not activate any IFN-α/β production, an amplified IFN-β response was observed when H/F-induced MGC were infected with a nonfusogenic recombinant chimerical virus. Time lapse microscopy studies revealed that MeV-infected MGC from epithelial cells have a highly dynamic behavior and an unexpected long life span. Following cell-cell fusion, both of the RIG-I and IFN-β gene deficiencies were trans complemented to induce IFN-β production. Production of IFN-β and IFN-α was also observed in MeV-infected immature dendritic cells (iDC) and mature dendritic cells (mDC). In contrast to iDC, MeV infection of mDC induced MGC, which produced enhanced amounts of IFN-α/β. The amplification of IFN-β production was associated with a sustained nuclear localization of IFN regulatory factor 3 (IRF-3) in MeV-induced MGC derived from both epithelial cells and mDC, while the IRF-7 up-regulation was poorly sensitive to the fusion process. Therefore, MeV-induced cell-cell fusion amplifies IFN-α/β production in infected cells, and this indicates that MGC contribute to the antiviral immune response.

Published
2007
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