title: A RIG-I 2CARD-MAVS200 Chimeric Protein Reconstitutes IFN-β Induction and Antiviral Response in Models Deficient in Type I IFN Response.
abstract: RIG-I-like receptors (RLRs) are cellular sensor proteins that detect certain RNA species produced during viral infections. RLRs activate a signaling cascade that results in the production of IFN-β as well as several other cytokines with antiviral and proinflammatory activities. We explored the potential of different constructs based on RLRs to induce the IFN-β pathway and create an antiviral state in type I IFN-unresponsive models. A chimeric construct composed of RIG-I 2CARD and the first 200 amino acids of MAVS (2CARD-MAVS200) showed an enhanced ability to induce IFN-β when compared to other stimulatory constructs. Furthermore, this human chimeric construct showed a superior ability to activate IFN-β expression in cells from various species. This construct was found to overcome the restrictions of blocking IFN-β induction or signaling by a number of viral IFN-antagonist proteins. Additionally, the antiviral activity of this chimera was demonstrated in influenza virus and HBV infection mouse models using adeno-associated virus (AAV) vectors as a delivery vehicle. We propose that AAV vectors expressing 2CARD-MAVS200 chimeric protein can reconstitute IFN-β induction and recover a partial antiviral state in different models that do not respond to recombinant IFN-β treatment.
authors.affiliation: Centro de Investigacix00F3;n Mx00E9;dica Aplicada, Gene Therapy and Regulation of Gene Expression Program, University of Navarra, Pamplona, Spain.
authors.forename: Estanislao
authors.initials: E
authors.lastname: Nistal-Villán
authors.forename: Estefanía
authors.initials: E
authors.lastname: Rodríguez-García
authors.forename: Marianna
authors.initials: M
authors.lastname: Di Scala
authors.forename: Roberto
authors.initials: R
authors.lastname: Ferrero-Laborda
authors.forename: Cristina
authors.initials: C
authors.lastname: Olagüe
authors.forename: África
authors.initials: Á
authors.lastname: Vales
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carte-Abad
authors.forename: Irene
authors.initials: I
authors.lastname: Crespo
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Esther
authors.initials: E
authors.lastname: Larrea
authors.forename: Gloria
authors.initials: G
authors.lastname: González-Aseguinolaza
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007113:Immunity, Innate; D009980:Influenza A virus / Q000276:immunology*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000628:therapy*; D010446:Peptide Fragments / Q000235:genetics; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D010446:Peptide Fragments; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D016899:Interferon-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases