title: Evidence for a Novel Mechanism of Influenza Virus-Induced Type I Interferon Expression by a Defective RNA-Encoded Protein.
abstract: Influenza A virus (IAV) defective RNAs are generated as byproducts of error-prone viral RNA replication. They are commonly derived from the larger segments of the viral genome and harbor deletions of various sizes resulting in the generation of replication incompatible viral particles. Furthermore, small subgenomic RNAs are known to be strong inducers of pattern recognition receptor RIG-I-dependent type I interferon (IFN) responses. The present study identifies a novel IAV-induced defective RNA derived from the PB2 segment of A/Thailand/1(KAN-1)/2004 (H5N1). It encodes a 10 kDa protein (PB2∆) sharing the N-terminal amino acid sequence of the parental PB2 protein followed by frame shift after internal deletion. PB2∆ induces the expression of IFNβ and IFN-stimulated genes by direct interaction with the cellular adapter protein MAVS, thereby reducing viral replication of IFN-sensitive viruses such as IAV or vesicular stomatitis virus. This induction of IFN is completely independent of the defective RNA itself that usually serves as pathogen-associated pattern and thus does not require the cytoplasmic sensor RIG-I. These data suggest that not only defective RNAs, but also some defective RNA-encoded proteins can act immunostimulatory. In this particular case, the KAN-1-induced defective RNA-encoded protein PB2∆ enhances the overwhelming immune response characteristic for highly pathogenic H5N1 viruses, leading to a more severe phenotype in vivo.
authors.affiliation: Institute of Molecular Virology (IMV), Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Boergeling
authors.affiliation: Institute of Experimental Pathology, Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany.
authors.forename: Timofey S
authors.initials: TS
authors.lastname: Rozhdestvensky
authors.affiliation: Institute of Molecular Virology (IMV), Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany.
authors.forename: Mirco
authors.initials: M
authors.lastname: Schmolke
authors.affiliation: Viral Zoonosis and Adaptation, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Resa-Infante
authors.affiliation: Institute of Experimental Pathology, Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Robeck
authors.affiliation: Institute of Experimental Pathology, Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Randau
authors.affiliation: Division of Influenza Viruses and Other Respiratory Viruses, Robert Koch Institute, Berlin, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wolff
authors.affiliation: Viral Zoonosis and Adaptation, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Gülsah
authors.initials: G
authors.lastname: Gabriel
authors.affiliation: Institute of Experimental Pathology, Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany; Institute of Evolutionary and Medical Genomics, Brandenburg Medical School (MHB), Neuruppin, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brosius
authors.affiliation: Institute of Molecular Virology (IMV), Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany; Interdisciplinary Center of Clinical Research (IZKF), Medical Faculty, University of Muenster, Muenster, Germany; Cells-in-Motion Cluster of Excellence, University of Muenster, Muenster, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D006386:Hemagglutination Tests; D047468:Immunoprecipitation; D009980:Influenza A virus / Q000502:physiology*; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000378:metabolism* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D007370:Interferon Type I; C057027:PB2 protein, Influenzavirus A; D012333:RNA, Messenger; D012367:RNA, Viral; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase