title: Hepatitis C virus pathogen associated molecular pattern (PAMP) triggers production of lambda-interferons by human plasmacytoid dendritic cells.
abstract: Plasmacytoid Dendritic Cells (pDCs) represent a key immune cell in the defense against viruses. Through pattern recognition receptors (PRRs), these cells detect viral pathogen associated molecular patterns (PAMPs) and initiate an Interferon (IFN) response. pDCs produce the antiviral IFNs including the well-studied Type I and the more recently described Type III. Recent genome wide association studies (GWAS) have implicated Type III IFNs in HCV clearance. We examined the IFN response induced in a pDC cell line and ex vivo human pDCs by a region of the HCV genome referred to as the HCV PAMP. This RNA has been shown previously to be immunogenic in hepatocytes, whereas the conserved X-region RNA is not. We show that in response to the HCV PAMP, pDC-GEN2.2 cells upregulate and secrete Type III (in addition to Type I) IFNs and upregulate PRR genes and proteins. We also demonstrate that the recognition of this RNA is dependent on RIG-I-like Receptors (RLRs) and Toll-like Receptors (TLRs), challenging the dogma that RLRs are dispensable in pDCs. The IFNs produced by these cells in response to the HCV PAMP also control HCV replication in vitro. These data are recapitulated in ex vivo pDCs isolated from healthy donors. Together, our data shows that pDCs respond robustly to HCV RNA to make Type III Interferons that control viral replication. This may represent a novel therapeutic strategy for the treatment of HCV.
authors: Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America.
authors: Amy E L
authors: AE
authors: Stone
authors: Silvia
authors: S
authors: Giugliano
authors: Gretja
authors: G
authors: Schnell
authors: Linling
authors: L
authors: Cheng
authors: Katelyn F
authors: KF
authors: Leahy
authors: Lucy
authors: L
authors: Golden-Mason
authors: Michael
authors: M
authors: Gale
authors: Hugo R
authors: HR
authors: Rosen
mesh_terms: D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis*; D007372:Interferons; D007378:Interleukins / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D012367:RNA, Viral / Q000276:immunology; D018168:Receptors, Retinoic Acid; D051193:Toll-Like Receptors / Q000378:metabolism; D014779:Virus Replication; D000095022:Interferon Lambda
chemical_list: D017077:Culture Media, Conditioned; D007370:Interferon Type I; D007372:Interferons; D007378:Interleukins; D034741:RNA, Small Interfering; D012367:RNA, Viral; D018168:Receptors, Retinoic Acid; D051193:Toll-Like Receptors; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C437968:PLAAT4 protein, human
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