title: Processing of genome 5' termini as a strategy of negative-strand RNA viruses to avoid RIG-I-dependent interferon induction.
abstract: Innate immunity is critically dependent on the rapid production of interferon in response to intruding viruses. The intracellular pathogen recognition receptors RIG-I and MDA5 are essential for interferon induction by viral RNAs containing 5' triphosphates or double-stranded structures, respectively. Viruses with a negative-stranded RNA genome are an important group of pathogens causing emerging and re-emerging diseases. We investigated the ability of genomic RNAs from substantial representatives of this virus group to induce interferon via RIG-I or MDA5. RNAs isolated from particles of Ebola virus, Nipah virus, Lassa virus, and Rift Valley fever virus strongly activated the interferon-beta promoter. Knockdown experiments demonstrated that interferon induction depended on RIG-I, but not MDA5, and phosphatase treatment revealed a requirement for the RNA 5' triphosphate group. In contrast, genomic RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus did not trigger interferon induction. Sensitivity of these RNAs to a 5' monophosphate-specific exonuclease indicates that the RIG-I-activating 5' triphosphate group was removed post-transcriptionally by a viral function. Consequently, RIG-I is unable to bind the RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus. These results establish RIG-I as a major intracellular recognition receptor for the genome of most negative-strand RNA viruses and define the cleavage of triphosphates at the RNA 5' end as a strategy of viruses to evade the innate immune response.
authors.affiliation: Department of Virology, University of Freiburg, Freiburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Habjan
authors.forename: Ida
authors.initials: I
authors.lastname: Andersson
authors.forename: Jonas
authors.initials: J
authors.lastname: Klingström
authors.forename: Michael
authors.initials: M
authors.lastname: Schümann
authors.forename: Arnold
authors.initials: A
authors.lastname: Martin
authors.forename: Petra
authors.initials: P
authors.lastname: Zimmermann
authors.forename: Valentina
authors.initials: V
authors.lastname: Wagner
authors.forename: Andreas
authors.initials: A
authors.lastname: Pichlmair
authors.forename: Urs
authors.initials: U
authors.lastname: Schneider
authors.forename: Elke
authors.initials: E
authors.lastname: Mühlberger
authors.forename: Ali
authors.initials: A
authors.lastname: Mirazimi
authors.forename: Friedemann
authors.initials: F
authors.lastname: Weber
mesh_terms: D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology*; D016679:Genome, Viral / Q000235:genetics*; D006801:Humans; D007372:Interferons / Q000276:immunology*; D010710:Phosphates; D012328:RNA Viruses / Q000235:genetics* / Q000472:pathogenicity; D012367:RNA, Viral / Q000235:genetics; D011971:Receptors, Immunologic; D014774:Virulence
chemical_list: D010710:Phosphates; D012367:RNA, Viral; D011971:Receptors, Immunologic; D007372:Interferons; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases