title: Lloviu virus VP24 and VP35 proteins function as innate immune antagonists in human and bat cells.
abstract: Lloviu virus (LLOV) is a new member of the filovirus family that also includes Ebola virus (EBOV) and Marburg virus (MARV). LLOV has not been cultured; however, its genomic RNA sequence indicates the coding capacity to produce homologs of the EBOV and MARV VP24, VP35, and VP40 proteins. EBOV and MARV VP35 proteins inhibit interferon (IFN)-alpha/beta production and EBOV VP35 blocks activation of the antiviral kinase PKR. The EBOV VP24 and MARV VP40 proteins inhibit IFN signaling, albeit by different mechanisms. Here we demonstrate that LLOV VP35 suppresses Sendai virus induced IFN regulatory factor 3 (IRF3) phosphorylation, IFN-α/β production, and PKR phosphorylation. Additionally, LLOV VP24 blocks tyrosine phosphorylated STAT1 binding to karyopherin alpha 5 (KPNA5), STAT1 nuclear accumulation, and IFN-induced gene expression. LLOV VP40 lacks detectable IFN antagonist function. These activities parallel EBOV IFN inhibitory functions. EBOV and LLOV VP35 and VP24 proteins also inhibit IFN responses in bat cells. These data suggest that LLOV infection will block innate immune responses in a manner similar to EBOV.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Feagins
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: chris.basler@mssm.edu.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
mesh_terms: D000818:Animals; D002460:Cell Line; D002685:Chiroptera / Q000821:virology*; D016563:Filoviridae / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D010766:Phosphorylation; D011485:Protein Binding; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D029082:Sendai virus / Q000235:genetics / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics* / Q000276:immunology; D028901:alpha Karyopherins / Q000235:genetics / Q000276:immunology; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; C000596544:KPNA5 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C446938:VP24 protein, Ebola virus; C080980:VP35 protein, filovirus; C080981:VP40 protein, virus; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; D028901:alpha Karyopherins; D016899:Interferon-beta; D019892:eIF-2 Kinase
keywords: Filovirus; Innate immune response; Interferon; Interferon antagonist; Lloviu virus