Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA.
Innate immune defences are essential for the control of virus infection and are triggered through host recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs). Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million people worldwide. Infection is regulated by hepatic immune defences triggered by the cellular RIG-I helicase. RIG-I binds PAMP RNA and signals interferon regulatory factor 3 activation to induce the expression of interferon-alpha/beta and antiviral/interferon-stimulated genes (ISGs) that limit infection. Here we identify the polyuridine motif of the HCV genome 3' non-translated region and its replication intermediate as the PAMP substrate of RIG-I, and show that this and similar homopolyuridine or homopolyriboadenine motifs present in the genomes of RNA viruses are the chief feature of RIG-I recognition and immune triggering in human and murine cells. 5' terminal triphosphate on the PAMP RNA was necessary but not sufficient for RIG-I binding, which was primarily dependent on homopolymeric ribonucleotide composition, linear structure and length. The HCV PAMP RNA stimulated RIG-I-dependent signalling to induce a hepatic innate immune response in vivo, and triggered interferon and ISG expression to suppress HCV infection in vitro. These results provide a conceptual advance by defining specific homopolymeric RNA motifs within the genome of HCV and other RNA viruses as the PAMP substrate of RIG-I, and demonstrate immunogenic features of the PAMP-RIG-I interaction that could be used as an immune adjuvant for vaccine and immunotherapy approaches.
Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98195-7650, USA.
Takeshi
T
Saito
David M
DM
Owen
Fuguo
F
Jiang
Joseph
J
Marcotrigiano
Michael
M
Gale
D000225:Adenine / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016679:Genome, Viral / Q000235:genetics; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008024:Ligands; D008099:Liver / Q000276:immunology / Q000821:virology; D051379:Mice; D012367:RNA, Viral / Q000235:genetics* / Q000276:immunology*; D014529:Uridine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics
D008024:Ligands; D012367:RNA, Viral; D016899:Interferon-beta; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000225:Adenine; D014529:Uridine