title: Identification of critical amino acids within the nucleoprotein of Tacaribe virus important for anti-interferon activity.
abstract: The arenavirus nucleoprotein (NP) can suppress induction of type I interferon (IFN). This anti-IFN activity is thought to be shared by all arenaviruses with the exception of Tacaribe virus (TCRV). To identify the TCRV NP amino acid residues that prevent its IFN-countering ability, we created a series of NP chimeras between residues of TCRV NP and Pichinde virus (PICV) NP, an arenavirus NP with potent anti-IFN function. Chimera NP analysis revealed that a minimal four amino acid stretch derived from PICV NP could impart efficient anti-IFN activity to TCRV NP. Strikingly, the TCRV NP gene cloned and sequenced from viral stocks obtained through National Institutes of Health Biodefense and Emerging Infections (BEI) resources deviated from the reference sequence at this particular four-amino acid region, GPPT (GenBank KC329849) versus DLQL (GenBank NC004293), respectively at residues 389-392. When efficiently expressed in cells through codon-optimization, TCRV NP containing the GPPT residues rescued the antagonistic IFN function. Consistent with cell expression results, TCRV infection did not stimulate an IFNβ response early in infection in multiple cells types (e.g. A549, P388D1), and IRF-3 was not translocated to the nucleus in TCRV-infected A549 cells. Collectively, these data suggest that certain TCRV strain variants contain the important NP amino acids necessary for anti-IFN activity.
authors: Sandia National Laboratories, Livermore, California 94550.
authors: Brooke
authors: B
authors: Harmon
authors: Sandia National Laboratories, Livermore, California 94550.
authors: Carol
authors: C
authors: Kozina
authors: Sandia National Laboratories, Livermore, California 94550.
authors: Dianna
authors: D
authors: Maar
authors: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California 94550.
authors: Timothy S
authors: TS
authors: Carpenter
authors: Sandia National Laboratories, Livermore, California 94550.
authors: Catherine S
authors: CS
authors: Branda
authors: Sandia National Laboratories, Livermore, California 94550. Electronic address: onegret@sandia.gov.
authors: Oscar A
authors: OA
authors: Negrete
authors: Sandia National Laboratories, Albuquerque, New Mexico 87123.
authors: Bryan D
authors: BD
authors: Carson
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D006477:Arenaviruses, New World / Q000276:immunology / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009698:Nucleoproteins / Q000096:biosynthesis / Q000737:chemistry* / Q000276:immunology; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000276:immunology; D015533:Transcriptional Activation; D014709:Vero Cells; D014764:Viral Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000276:immunology
chemical_list: D050838:Interferon Regulatory Factor-3; D009698:Nucleoproteins; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D016899:Interferon-beta
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