title: Viral suppressors of the RIG-I-mediated interferon response are pre-packaged in influenza virions.
abstract: The type I interferon (IFN) response represents the first line of defence to invading pathogens. Internalized viral ribonucleoproteins (vRNPs) of negative-strand RNA viruses induce an early IFN response by interacting with retinoic acid inducible gene I (RIG-I) and its recruitment to mitochondria. Here we employ three-dimensional stochastic optical reconstruction microscopy (STORM) to visualize incoming influenza A virus (IAV) vRNPs as helical-like structures associated with mitochondria. Unexpectedly, an early IFN induction in response to vRNPs is not detected. A distinct amino-acid motif in the viral polymerases, PB1/PA, suppresses early IFN induction. Mutation of this motif leads to reduced pathogenicity in vivo, whereas restoration increases it. Evolutionary dynamics in these sequences suggest that completion of the motif, combined with viral reassortment can contribute to pandemic risks. In summary, inhibition of the immediate anti-viral response is 'pre-packaged' in IAV in the sequences of vRNP-associated polymerase proteins.
authors.affiliation: Institute of Molecular Virology (IMV), Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Von-Esmarch-Street 56, D-48149 Muenster, Germany.
authors.forename: Swantje
authors.initials: S
authors.lastname: Liedmann
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA.
authors.forename: Eike R
authors.initials: ER
authors.lastname: Hrincius
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA.
authors.forename: Cliff
authors.initials: C
authors.lastname: Guy
authors.affiliation: Institute of Molecular Virology (IMV), Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Von-Esmarch-Street 56, D-48149 Muenster, Germany.
authors.forename: Darisuren
authors.initials: D
authors.lastname: Anhlan
authors.affiliation: Institute of Molecular Virology (IMV), Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Von-Esmarch-Street 56, D-48149 Muenster, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Dierkes
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Carter
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Institute of Virology, University Medical Center Freiburg, Hermann-Herder-Street 11, D-79104 Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Staeheli
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Division of Influenza and Other Respiratory Viruses, Seestraβe 10, Robert Koch-Institut, D-13353 Berlin, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wolff
authors.affiliation: 1] Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA [2] Department of Pediatrics, University of Tennessee Health Sciences Center, 50 N. Dunlap, Memphis, Tennessee 38103, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: McCullers
authors.affiliation: 1] Institute of Molecular Virology (IMV), Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Von-Esmarch-Street 56, D-48149 Muenster, Germany [2] Cluster of Excellence Cells in Motion, University of Muenster, Muenster, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
authors.affiliation: 1] Institute of Molecular Virology (IMV), Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Von-Esmarch-Street 56, D-48149 Muenster, Germany [2] Cluster of Excellence Cells in Motion, University of Muenster, Muenster, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Ehrhardt
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry*; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D009980:Influenza A virus / Q000472:pathogenicity*; D007370:Interferon Type I / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008928:Mitochondria / Q000821:virology*; D012328:RNA Viruses / Q000472:pathogenicity; D011971:Receptors, Immunologic; D019562:Viral Load; D014764:Viral Proteins / Q000737:chemistry; D014771:Virion / Q000737:chemistry*; D014774:Virulence
chemical_list: D007370:Interferon Type I; D011971:Receptors, Immunologic; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases