title: Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins.
abstract: Suppression of innate immune responses during filoviral infection contributes to disease severity. Ebola (EBOV) and Marburg (MARV) viruses each encode a VP35 protein that suppresses RIG-I-like receptor signaling and interferon-α/β (IFN-α/β) production by several mechanisms, including direct binding to double stranded RNA (dsRNA). Here, we demonstrate that in cell culture, MARV infection results in a greater upregulation of IFN responses as compared to EBOV infection. This correlates with differences in the efficiencies by which EBOV and MARV VP35s antagonize RIG-I signaling. Furthermore, structural and biochemical studies suggest that differential recognition of RNA elements by the respective VP35 C-terminal IFN inhibitory domain (IID) rather than affinity for RNA by the respective VP35s is critical for this observation. Our studies reveal functional differences in EBOV versus MARV VP35 RNA binding that result in unexpected differences in the host response to deadly viral pathogens.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Megan R
authors.initials: MR
authors.lastname: Edwards
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Gai
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Galveston National Laboratory, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Mire
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA.
authors.forename: Suhas
authors.initials: S
authors.lastname: Sureshchandra
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Luthra
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yen
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Virology Group, J. Craig Venter Institute, Rockville, MD 20850, USA.
authors.forename: Reed S
authors.initials: RS
authors.lastname: Shabman
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Daisy W
authors.initials: DW
authors.lastname: Leung
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA.
authors.forename: Ilhem
authors.initials: I
authors.lastname: Messaoudi
authors.affiliation: Department of Microbiology and Immunology, Galveston National Laboratory, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Geisbert
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: gamarasinghe@path.wustl.edu.
authors.forename: Gaya K
authors.initials: GK
authors.lastname: Amarasinghe
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: chris.basler@mssm.edu.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D029043:Ebolavirus / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D029024:Marburgvirus / Q000235:genetics* / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009000:Monocytes; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D011971:Receptors, Immunologic; D016415:Sequence Alignment; D015398:Signal Transduction; D013045:Species Specificity; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology
chemical_list: D016898:Interferon-alpha; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; C080980:VP35 protein, filovirus; D054334:Viral Regulatory and Accessory Proteins; D016899:Interferon-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
keywords: RIG-I like receptor; VP35; filovirus; immune evasion; pattern associated molecular pattern (PAMP); type I interferon