Processing of genome 5' termini as a strategy of negative-strand RNA viruses to avoid RIG-I-dependent interferon induction.
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.
Habjan
Matthias
M
Department of Virology, University of Freiburg, Freiburg, Germany.
Andersson
Ida
I
Klingström
Jonas
J
Schümann
Michael
M
Martin
Arnold
A
Zimmermann
Petra
P
Wagner
Valentina
V
Pichlmair
Andreas
A
Schneider
Urs
U
Mühlberger
Elke
E
Mirazimi
Ali
A
Weber
Friedemann
F
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
D010710:Phosphates; D012367:RNA, Viral; D011971:Receptors, Immunologic; D007372:Interferons; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases