Hepatitis C Virus Pathogen Associated Molecular Pattern (PAMP) Triggers Production of Lambda-Interferons by Human Plasmacytoid Dendritic Cells

PLoS Pathogens

Linling Cheng¹  Hugo R. Rosen²  Gretja Schnell²  Katelyn F. Leahy²  Lucy Golden-Mason²  Silvia Giugliano²  Amy E. L. Stone³  Michael Gale Jr³ 

[1] Department of Immunology, University of Washington, School of Medicine, Seattle, Washington, United States of America;Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America;Integrated Department in Immunology: University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America

关键词: Interferons;    Small interfering RNAs;    Hepatitis C virus;    Transfection;    Gene expression;    RNA isolation;    Viral replication;    Hepatocytes;   

DOI  :  10.1371/journal.ppat.1003316

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY