Base de dados : MEDLINE
Pesquisa : D08.811.913.696.445.735.720.249.875 [Categoria DeCS]
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[PMID]:28460448
[Au] Autor:Li L; Wang Q; Yang F; Wu C; Chen S; Wen X; Liu C; Li Y
[Ad] Endereço:Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
[Ti] Título:Anti-MDA5 antibody as a potential diagnostic and prognostic biomarker in patients with dermatomyositis.
[So] Source:Oncotarget;8(16):26552-26564, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The presence of anti-MDA5 antibodies in serum represents an important biomarker in the diagnosis and prediction of prognosis for patients with idiopathic inflammatory myopathies (IIMs). Due to conflicting results that have been reported regarding the detection of anti-MDA5 antibodies, the goal of this study was to assess a potential association between the presence of anti-MDA5 antibodies and dermatomyositis/polymyositis (DM/PM), as well as the diagnostic and prognostic values of anti-MDA5 antibodies for DM/PM. For this, a review of literature published prior to October 15, 2016 was conducted. Eight studies with 286 PM patients and 216 healthy controls and nine studies with 628 DM patients and 221 healthy controls were selected according to specific inclusion criteria. The outcomes of these studies revealed that the presence of anti-MDA5 antibodies was associated with DM, especially CADM, and not with PM. Furthermore, the pooled sensitivity, specificity, and area under the curve (AUC) values were 0.62 (95% confidence interval (CI): 0.52-0.70), 1.00 (95% CI: 0.97-1.00), and 0.9381 for CADM patients versus healthy controls when an immunoprecipitation method was used. The presence of anti-MDA5 antibodies was also found to be significantly associated with an increased risk of death in DM (relative risk = 3.32, 95% CI: 1.65-6.67, P = 0.001). These findings suggest that anti-MDA5 antibodies correlate with DM and could be used as a biomarker in the clinical diagnosis of CADM. The presence of anti-MDA5 antibodies was also associated with poor prognosis regarding the overall survival of patients with DM.
[Mh] Termos MeSH primário: Autoanticorpos/imunologia
Dermatomiosite/diagnóstico
Dermatomiosite/imunologia
Helicase IFIH1 Induzida por Interferon/imunologia
[Mh] Termos MeSH secundário: Autoanticorpos/sangue
Biomarcadores
Estudos de Casos e Controles
Suscetibilidade a Doenças
Ensaio de Imunoadsorção Enzimática
Feminino
Seres Humanos
Masculino
Razão de Chances
Prognóstico
Reprodutibilidade dos Testes
Risco
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Biomarkers); EC 3.6.1.- (IFIH1 protein, human); EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15716


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[PMID]:29186193
[Au] Autor:Sprokholt JK; Kaptein TM; van Hamme JL; Overmars RJ; Gringhuis SI; Geijtenbeek TBH
[Ad] Endereço:Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
[Ti] Título:RIG-I-like receptor activation by dengue virus drives follicular T helper cell formation and antibody production.
[So] Source:PLoS Pathog;13(11):e1006738, 2017 Nov.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Follicular T helper cells (TFH) are fundamental in orchestrating effective antibody-mediated responses critical for immunity against viral infections and effective vaccines. However, it is unclear how virus infection leads to TFH induction. We here show that dengue virus (DENV) infection of human dendritic cells (DCs) drives TFH formation via crosstalk of RIG-I-like receptor (RLR) RIG-I and MDA5 with type I Interferon (IFN) signaling. DENV infection leads to RLR-dependent IKKε activation, which phosphorylates IFNα/ß receptor-induced STAT1 to drive IL-27 production via the transcriptional complex ISGF3. Inhibiting RLR activation as well as neutralizing antibodies against IL-27 prevented TFH formation. DENV-induced CXCR5+PD-1+Bcl-6+ TFH cells secreted IL-21 and activated B cells to produce IgM and IgG. Notably, RLR activation by synthetic ligands also induced IL-27 secretion and TFH polarization. These results identify an innate mechanism by which antibodies develop during viral disease and identify RLR ligands as potent adjuvants for TFH-promoting vaccination strategies.
[Mh] Termos MeSH primário: Anticorpos Antivirais/imunologia
Vírus da Dengue/fisiologia
Dengue/imunologia
Linfócitos T Auxiliares-Indutores/imunologia
[Mh] Termos MeSH secundário: Formação de Anticorpos
Linfócitos B/imunologia
Proteína DEAD-box 58/genética
Proteína DEAD-box 58/imunologia
Células Dendríticas/imunologia
Dengue/genética
Dengue/virologia
Seres Humanos
Helicase IFIH1 Induzida por Interferon/genética
Helicase IFIH1 Induzida por Interferon/imunologia
Interleucina-27/genética
Interleucina-27/imunologia
Interleucinas/genética
Interleucinas/imunologia
Ativação Linfocitária
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Viral); 0 (Interleukin-27); 0 (Interleukins); 0 (interleukin-21); EC 3.6.1.- (DDX58 protein, human); EC 3.6.1.- (IFIH1 protein, human); EC 3.6.4.13 (DEAD Box Protein 58); EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006738


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[PMID]:28448848
[Au] Autor:Ding Z; An K; Xie L; Wu W; Zhang R; Wang D; Fang Y; Chen H; Xiao S; Fang L
[Ad] Endereço:State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; Key Laboratory of Preventive Veterinary Medicine in Hubei Province, the Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
[Ti] Título:Transmissible gastroenteritis virus infection induces NF-κB activation through RLR-mediated signaling.
[So] Source:Virology;507:170-178, 2017 07.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Transmissible gastroenteritis virus (TGEV) is a porcine enteric coronavirus which causes lethal severe watery diarrhea in piglets. The pathogenesis of TGEV is strongly associated with inflammation. In this study, we found that TGEV infection activates transcription factors NF-κB, IRF3 and AP-1 in a time- and dose-dependent manner in porcine kidney cells. Treatment with the NF-κB-specific inhibitor BAY11-7082 significantly decreased TGEV-induced proinflammatory cytokine production, but did not affect virus replication. Phosphorylation of NF-κB subunit p65 and proinflammatory cytokine production were greatly decreased after knockdown of retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) or its adaptors MAVS and STING, while only slight reduction was observed in cells following silencing of Toll-like receptor adaptors, MyD88 and TRIF. Furthermore, TGEV infection significantly upregulated mRNA expression of RIG-I and MDA5. Taken together, our results indicate that the RLR signaling pathway is involved in TGEV-induced inflammatory responses.
[Mh] Termos MeSH primário: Gastroenterite Suína Transmissível/imunologia
Gastroenterite Suína Transmissível/virologia
NF-kappa B/imunologia
Vírus da Gastroenterite Transmissível/fisiologia
[Mh] Termos MeSH secundário: Animais
Citocinas/genética
Citocinas/imunologia
Proteína DEAD-box 58/genética
Proteína DEAD-box 58/imunologia
Gastroenterite Suína Transmissível/genética
Helicase IFIH1 Induzida por Interferon/genética
Helicase IFIH1 Induzida por Interferon/imunologia
NF-kappa B/genética
Fosforilação
Transdução de Sinais
Suínos
Fator de Transcrição AP-1/genética
Fator de Transcrição AP-1/imunologia
Vírus da Gastroenterite Transmissível/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytokines); 0 (NF-kappa B); 0 (Transcription Factor AP-1); EC 3.6.4.13 (DEAD Box Protein 58); EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171220
[Lr] Data última revisão:
171220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE


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[PMID]:28900038
[Au] Autor:Blumer T; Coto-Llerena M; Duong FHT; Heim MH
[Ad] Endereço:From the Department of Biomedicine, University of Basel, 4031 Basel, Switzerland and.
[Ti] Título:SOCS1 is an inducible negative regulator of interferon λ (IFN-λ)-induced gene expression .
[So] Source:J Biol Chem;292(43):17928-17938, 2017 Oct 27.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Type I (α and ß) and type III (λ) IFNs are induced upon viral infection through host sensory pathways that activate IFN regulatory factors (IRFs) and nuclear factor κB. Secreted IFNs induce autocrine and paracrine signaling through the JAK-STAT pathway, leading to the transcriptional induction of hundreds of IFN-stimulated genes, among them sensory pathway components such as cGAS, STING, RIG-I, MDA5, and the transcription factor IRF7, which enhance the induction of IFN-αs and IFN-λs. This positive feedback loop enables a very rapid and strong host response that, at some point, has to be controlled by negative regulators to maintain tissue homeostasis. Type I IFN signaling is controlled by the inducible negative regulators suppressor of cytokine signaling 1 (SOCS1), SOCS3, and ubiquitin-specific peptidase 18 (USP18). The physiological role of these proteins in IFN-γ signaling has not been clarified. Here we used knockout cell lines and mice to show that IFN-λ signaling is regulated by SOCS1 but not by SOCS3 or USP18. These differences were the basis for the distinct kinetic properties of type I and III IFNs. We found that IFN-α signaling is transient and becomes refractory after hours, whereas IFN-λ provides a long-lasting IFN-stimulated gene induction.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica/fisiologia
Interferons/metabolismo
Transdução de Sinais/fisiologia
Proteína 1 Supressora da Sinalização de Citocina/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Proteína DEAD-box 58/genética
Proteína DEAD-box 58/metabolismo
Endopeptidases/genética
Endopeptidases/metabolismo
Seres Humanos
Helicase IFIH1 Induzida por Interferon/genética
Helicase IFIH1 Induzida por Interferon/metabolismo
Interferons/genética
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos
Camundongos Knockout
Nucleotidiltransferases/genética
Nucleotidiltransferases/metabolismo
Proteína 1 Supressora da Sinalização de Citocina/genética
Proteína 3 Supressora da Sinalização de Citocinas/genética
Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
Ubiquitina Tiolesterase/genética
Ubiquitina Tiolesterase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MPYS protein, human); 0 (MPYS protein, mouse); 0 (Membrane Proteins); 0 (SOCS1 protein, human); 0 (SOCS3 protein, human); 0 (Socs1 protein, mouse); 0 (Socs3 protein, mouse); 0 (Suppressor of Cytokine Signaling 1 Protein); 0 (Suppressor of Cytokine Signaling 3 Protein); 9008-11-1 (Interferons); EC 2.7.7.- (MB21D1 protein, human); EC 2.7.7.- (MB21D1 protein, mouse); EC 2.7.7.- (Nucleotidyltransferases); EC 3.4.- (Endopeptidases); EC 3.4.19.- (Usp18 protein, mouse); EC 3.4.19.12 (Ubiquitin Thiolesterase); EC 3.4.99.- (USP18 protein, human); EC 3.6.1.- (DDX58 protein, human); EC 3.6.1.- (Ddx58 protein, mouse); EC 3.6.1.- (IFIH1 protein, human); EC 3.6.1.- (Ifih1 protein, mouse); EC 3.6.4.13 (DEAD Box Protein 58); EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170914
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.788877


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[PMID]:28851763
[Au] Autor:Dou Y; Yim HC; Kirkwood CD; Williams BR; Sadler AJ
[Ad] Endereço:Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Vic., Australia.
[Ti] Título:The innate immune receptor MDA5 limits rotavirus infection but promotes cell death and pancreatic inflammation.
[So] Source:EMBO J;36(18):2742-2757, 2017 Sep 15.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Melanoma differentiation-associated protein 5 (MDA5) mediates the innate immune response to viral infection. Polymorphisms in , the gene coding for MDA5, correlate with the risk of developing type 1 diabetes (T1D). Here, we demonstrate that MDA5 is crucial for the immune response to enteric rotavirus infection, a proposed etiological agent for T1D. MDA5 variants encoded by minor alleles associated with lower T1D risk exhibit reduced activity against rotavirus infection. We find that MDA5 activity limits rotavirus infection not only through the induction of antiviral interferons and pro-inflammatory cytokines, but also by promoting cell death. Importantly, this MDA5-dependent antiviral response is specific to the pancreas of rotavirus-infected mice, similar to the autoimmunity associated with T1D. These findings imply that MDA5-induced cell death and inflammation in the pancreas facilitate progression to autoimmune destruction of pancreatic ß-cells.
[Mh] Termos MeSH primário: Morte Celular
Interações Hospedeiro-Patógeno
Helicase IFIH1 Induzida por Interferon/metabolismo
Pâncreas/patologia
Infecções por Rotavirus/imunologia
Infecções por Rotavirus/patologia
Rotavirus/patogenicidade
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Inflamação/patologia
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.6.1.- (Ifih1 protein, mouse); EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170831
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201696273


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[PMID]:28848065
[Au] Autor:Kasumba DM; Hajake T; Oh SW; Kotenko SV; Kato H; Fujita T
[Ad] Endereço:Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507 Japan.
[Ti] Título:A Plant-Derived Nucleic Acid Reconciles Type I IFN and a Pyroptotic-like Event in Immunity against Respiratory Viruses.
[So] Source:J Immunol;199(7):2460-2474, 2017 Oct 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nucleic acids carrying pathogen-associated molecular patterns trigger innate immune responses and are used to activate host immunity. Although synthetic nucleic acids have been used for that purpose, they have shown limitations for in vivo and clinical applications. To address this issue, we tested a naturally occurring dsRNA extracted from rice bran (rb-dsRNA) and characterized it as a potent ligand of TLR3 and MDA5. In this study, intranasal administration of rb-dsRNA induced production of type I IFNs by alveolar macrophages and protected mice from morbidity and mortality resulting from respiratory virus infection, such as influenza A virus. This protection was completely absent in mice lacking both TRIF and MDA5, indicating the essential role of TLR3- and MDA5-dependent pathways. Interestingly, IFNAR1-deficient mice retained residual antiviral protection, which was abolished by pharmacological inhibition of caspase 1, but not IL-1ß signaling. In fact, rb-dsRNA activated caspase 1 via TRIF, resulting in the release of IL-1ß and LDH. In addition to the direct antiviral activity, rb-dsRNA modulated the immune cell population in the lungs by repopulating virus-depleted alveolar macrophages. Our data demonstrate that rb-dsRNA orchestrates IFN-dependent and -independent direct antiviral protection and that it is a potent immune stimulator modulating antiviral immunity in the lungs. These findings open doors to a range of precise immune-modulating studies and therapeutic options.
[Mh] Termos MeSH primário: Antivirais/isolamento & purificação
Vírus da Influenza A/imunologia
Interferon Tipo I/imunologia
Infecções por Orthomyxoviridae/imunologia
Oryza/genética
RNA de Cadeia Dupla/imunologia
RNA de Cadeia Dupla/isolamento & purificação
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/deficiência
Proteínas Adaptadoras de Transporte Vesicular/genética
Animais
Antivirais/imunologia
Inibidores de Caspase/administração & dosagem
Imunidade Inata
Interferon Tipo I/biossíntese
Helicase IFIH1 Induzida por Interferon/química
Helicase IFIH1 Induzida por Interferon/deficiência
Helicase IFIH1 Induzida por Interferon/genética
Interleucina-1beta/antagonistas & inibidores
Interleucina-1beta/metabolismo
Interleucina-1beta/secreção
Ligantes
Pulmão/imunologia
Pulmão/virologia
Macrófagos Alveolares/efeitos dos fármacos
Macrófagos Alveolares/imunologia
Camundongos
Infecções por Orthomyxoviridae/prevenção & controle
Oryza/química
Plantas/química
Plantas/genética
RNA de Cadeia Dupla/administração & dosagem
RNA de Cadeia Dupla/farmacologia
Receptor de Interferon alfa e beta/deficiência
Transdução de Sinais/efeitos dos fármacos
Receptor 3 Toll-Like/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Antiviral Agents); 0 (Caspase Inhibitors); 0 (IL1B protein, mouse); 0 (Ifnar1 protein, mouse); 0 (Interferon Type I); 0 (Interleukin-1beta); 0 (Ligands); 0 (RNA, Double-Stranded); 0 (TICAM-1 protein, mouse); 0 (Toll-Like Receptor 3); 156986-95-7 (Receptor, Interferon alpha-beta); EC 3.6.1.- (Ifih1 protein, mouse); EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170830
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700523


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[PMID]:28768856
[Au] Autor:Mura M; Combredet C; Najburg V; Sanchez David RY; Tangy F; Komarova AV
[Ad] Endereço:Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR-3569, Paris, France.
[Ti] Título:Nonencapsidated 5' Copy-Back Defective Interfering Genomes Produced by Recombinant Measles Viruses Are Recognized by RIG-I and LGP2 but Not MDA5.
[So] Source:J Virol;91(20), 2017 Oct 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Attenuated measles virus (MV) is one of the most effective and safe vaccines available, making it an attractive candidate vector for preventing other infectious diseases. Yet the great capacity of this vaccine still needs to be understood at the molecular level. MV vaccine strains have different type I interferon (IFN)-inducing abilities that partially depend on the presence of 5' copy-back defective interfering genomes (DI-RNAs). DI-RNAs are pathogen-associated molecular patterns recognized by RIG-I-like receptors (RLRs) (RIG-I, MDA5, and LGP2) that activate innate immune signaling and shape the adaptive immune response. In this study, we characterized the DI-RNAs produced by various modified recombinant MVs (rMVs), including vaccine candidates, as well as wild-type MV. All tested rMVs produced 5' copy-back DI-RNAs that were different in length and nucleotide sequence but still respected the so-called "rule of six." We correlated the presence of DI-RNAs with a larger stimulation of the IFN-ß pathway and compared their immunostimulatory potentials. Importantly, we revealed that encapsidation of DI-RNA molecules within the MV nucleocapsid abolished their immunoactive properties. Furthermore, we identified specific interactions of DI-RNAs with both RIG-I and LGP2 but not MDA5. Our results suggest that DI-RNAs produced by rMV vaccine candidates may indeed strengthen their efficiency by triggering RLR signaling. Having been administered to hundreds of millions of children, the live attenuated measles virus (MV) vaccine is the safest and most widely used human vaccine, providing high protection with long-term memory. Additionally, recombinant MVs carrying heterologous antigens are promising vectors for new vaccines. The great capacity of this vaccine still needs to be elucidated at the molecular level. Here we document that recombinant MVs produce defective interfering genomes that have high immunostimulatory properties via their binding to RIG-I and LGP2 proteins, both of which are cytosolic nonself RNA sensors of innate immunity. Defective interfering genome production during viral replication should be considered of great importance due to the immunostimulatory properties of these genomes as intrinsic adjuvants produced by the vector that increase recognition by the innate immune system.
[Mh] Termos MeSH primário: Genoma Viral
Helicase IFIH1 Induzida por Interferon/metabolismo
Vírus do Sarampo/genética
RNA Helicases/metabolismo
RNA Viral/genética
RNA Viral/metabolismo
Receptores do Ácido Retinoico/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Seres Humanos
Imunidade Inata
Interferon beta/metabolismo
Sarampo/virologia
Vacina contra Sarampo/genética
Vacina contra Sarampo/imunologia
Vírus do Sarampo/patogenicidade
Nucleocapsídeo/metabolismo
RNA Viral/imunologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Measles Vaccine); 0 (RARRES3 protein, human); 0 (RNA, Viral); 0 (Receptors, Retinoic Acid); 77238-31-4 (Interferon-beta); EC 2.7.7.- (DHX58 protein, human); EC 3.6.1.- (IFIH1 protein, human); EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1); EC 3.6.4.13 (RNA Helicases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE


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[PMID]:28760879
[Au] Autor:Lui PY; Wong LR; Ho TH; Au SWN; Chan CP; Kok KH; Jin DY
[Ad] Endereço:School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
[Ti] Título:PACT Facilitates RNA-Induced Activation of MDA5 by Promoting MDA5 Oligomerization.
[So] Source:J Immunol;199(5):1846-1855, 2017 Sep 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:MDA5 is a RIG-I-like cytoplasmic sensor of dsRNA and certain RNA viruses, such as encephalomyocarditis virus, for the initiation of the IFN signaling cascade in the innate antiviral response. The affinity of MDA5 toward dsRNA is low, and its activity becomes optimal in the presence of unknown cellular coactivators. In this article, we report an essential coactivator function of dsRNA-binding protein PACT in mediating the MDA5-dependent type I IFN response. Virus-induced and polyinosinic-polycytidylic acid-induced activation of MDA5 were severely impaired in PACT-knockout cells and attenuated in PACT-knockdown cells, but they were potentiated when PACT was overexpressed. PACT augmented IRF3-dependent type I IFN production subsequent to dsRNA-induced activation of MDA5. In contrast, PACT had no influence on MDA5-mediated activation of NF-κB. PACT required dsRNA interaction for its action on MDA5 and promoted dsRNA-induced oligomerization of MDA5. PACT had little stimulatory effect on MDA5 mutants deficient for oligomerization and filament assembly. PACT colocalized with MDA5 in the cytoplasm and potentiated MDA5 recruitment to the dsRNA ligand. Taken together, these findings suggest that PACT functions as an essential cellular coactivator of RIG-I, as well as MDA5, and it facilitates RNA-induced formation of MDA5 oligomers.
[Mh] Termos MeSH primário: Infecções por Cardiovirus/imunologia
Vírus da Encefalomiocardite/fisiologia
Helicase IFIH1 Induzida por Interferon/metabolismo
RNA de Cadeia Dupla/imunologia
Proteínas de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas
Técnicas de Silenciamento de Genes
Células HEK293
Seres Humanos
Imunidade Inata
Fator Regulador 3 de Interferon/genética
Fator Regulador 3 de Interferon/metabolismo
Interferon Tipo I/metabolismo
Helicase IFIH1 Induzida por Interferon/genética
Mutação/genética
Poli I-C/imunologia
Polimerização
Proteínas de Ligação a RNA/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IRF3 protein, human); 0 (Interferon Regulatory Factor-3); 0 (Interferon Type I); 0 (PRKRA protein, human); 0 (RNA, Double-Stranded); 0 (RNA-Binding Proteins); EC 3.6.1.- (IFIH1 protein, human); EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1); O84C90HH2L (Poly I-C)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601493


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[PMID]:28659477
[Au] Autor:Zhang HL; Ye HQ; Liu SQ; Deng CL; Li XD; Shi PY; Zhang B
[Ad] Endereço:Chinese Academy of Sciences Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
[Ti] Título:West Nile Virus NS1 Antagonizes Interferon Beta Production by Targeting RIG-I and MDA5.
[So] Source:J Virol;91(18), 2017 Sep 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:West Nile virus (WNV) is a mosquito-borne flavivirus that causes epidemics of encephalitis and viscerotropic disease worldwide. This virus has spread rapidly and has posed a significant public health threat since the outbreak in New York City in 1999. The interferon (IFN)-mediated antiviral response represents an important component of virus-host interactions and plays an essential role in regulating viral replication. Previous studies have suggested that multifunctional nonstructural proteins encoded by flaviviruses antagonize the host IFN response via various means in order to establish efficient viral replication. In this study, we demonstrated that the nonstructural protein 1 (NS1) of WNV antagonizes IFN-ß production, most likely through suppression of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) activation. In a dual-luciferase reporter assay, WNV NS1 significantly inhibited the activation of the IFN-ß promoter after Sendai virus infection or poly(I·C) treatment. NS1 also suppressed the activation of the IFN-ß promoter when it was stimulated by interferon regulatory factor 3 (IRF3)/5D or its upstream molecules in the RLR signaling pathway. Furthermore, NS1 blocked the phosphorylation and nuclear translocation of IRF3 upon stimulation by various inducers. Mechanistically, WNV NS1 targets RIG-I and melanoma differentiation-associated gene 5 (MDA5) by interacting with them and subsequently causing their degradation by the proteasome. Furthermore, WNV NS1 inhibits the K63-linked polyubiquitination of RIG-I, thereby inhibiting the activation of downstream sensors in the RLR signaling pathway. Taken together, our results reveal a novel mechanism by which WNV NS1 interferes with the host antiviral response. WNV Nile virus (WNV) has received increased attention since its introduction to the United States. However, the pathogenesis of this virus is poorly understood. This study demonstrated that the nonstructural protein 1 (NS1) of WNV antagonizes the induction of interferon beta (IFN-ß) by interacting with and degrading retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), which are crucial viral sensors in the host innate immune system. Further experiments suggested that NS1-mediated inhibition of the RIG-I-like receptor (RLR) signaling pathway involves inhibition of RIG-I K63-linked polyubiquitination and that the proteasome plays a role in RIG-I degradation. This study provides new insights into the regulation of WNV NS1 in the RLR signaling pathway and reveals a novel mechanism by which WNV evades the host innate immune response. The novel findings may guide us to discover new therapeutic targets and develop effective vaccines for WNV infections.
[Mh] Termos MeSH primário: Proteína DEAD-box 58/metabolismo
Interações Hospedeiro-Patógeno
Evasão da Resposta Imune
Helicase IFIH1 Induzida por Interferon/metabolismo
Interferon beta/antagonistas & inibidores
Proteínas não Estruturais Virais/metabolismo
Vírus do Nilo Ocidental/patogenicidade
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Seres Humanos
Complexo de Endopeptidases do Proteassoma/metabolismo
Proteólise
Vírus do Nilo Ocidental/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Viral Nonstructural Proteins); 0 (nonstructural protein 1, West Nile virus); 77238-31-4 (Interferon-beta); EC 3.4.25.1 (Proteasome Endopeptidase Complex); EC 3.6.1.- (DDX58 protein, human); EC 3.6.1.- (IFIH1 protein, human); EC 3.6.4.13 (DEAD Box Protein 58); EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE


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[PMID]:28606988
[Au] Autor:Lamborn IT; Jing H; Zhang Y; Drutman SB; Abbott JK; Munir S; Bade S; Murdock HM; Santos CP; Brock LG; Masutani E; Fordjour EY; McElwee JJ; Hughes JD; Nichols DP; Belkadi A; Oler AJ; Happel CS; Matthews HF; Abel L; Collins PL; Subbarao K; Gelfand EW; Ciancanelli MJ; Casanova JL; Su HC
[Ad] Endereço:Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
[Ti] Título:Recurrent rhinovirus infections in a child with inherited MDA5 deficiency.
[So] Source:J Exp Med;214(7):1949-1972, 2017 Jul 03.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:MDA5 is a cytosolic sensor of double-stranded RNA (ds)RNA including viral byproducts and intermediates. We studied a child with life-threatening, recurrent respiratory tract infections, caused by viruses including human rhinovirus (HRV), influenza virus, and respiratory syncytial virus (RSV). We identified in her a homozygous missense mutation in that encodes MDA5. Mutant MDA5 was expressed but did not recognize the synthetic MDA5 agonist/(ds)RNA mimic polyinosinic-polycytidylic acid. When overexpressed, mutant MDA5 failed to drive luciferase activity from the promoter or promoters containing ISRE or NF-κB sequence motifs. In respiratory epithelial cells or fibroblasts, wild-type but not knockdown of MDA5 restricted HRV infection while increasing IFN-stimulated gene expression and IFN-ß/λ. However, wild-type MDA5 did not restrict influenza virus or RSV replication. Moreover, nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. Thus, human MDA5 deficiency is a novel inborn error of innate and/or intrinsic immunity that causes impaired (ds)RNA sensing, reduced IFN induction, and susceptibility to the common cold virus.
[Mh] Termos MeSH primário: Helicase IFIH1 Induzida por Interferon/genética
Mutação
Infecções por Picornaviridae/genética
Infecções por Picornaviridae/virologia
Rhinovirus/fisiologia
[Mh] Termos MeSH secundário: Antivirais/farmacologia
Sequência de Bases
Células Cultivadas
Pré-Escolar
Análise Mutacional de DNA/métodos
Feminino
Fibroblastos/efeitos dos fármacos
Fibroblastos/metabolismo
Fibroblastos/virologia
Expressão Gênica/efeitos dos fármacos
Genes Recessivos/genética
Heterozigoto
Homozigoto
Interações Hospedeiro-Patógeno
Seres Humanos
Helicase IFIH1 Induzida por Interferon/deficiência
Interferons/farmacologia
Masculino
Linhagem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 9008-11-1 (Interferons); EC 3.6.1.- (IFIH1 protein, human); EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE
[do] DOI:10.1084/jem.20161759



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