Hepatitis C virus core protein inhibits interferon production by a human plasmacytoid dendritic cell line and dysregulates interferon regulatory factor-7 and signal transducer and activator of transcription (STAT) 1 protein expression.
Plasmacytoid Dendritic Cells (pDCs) represent a key immune cell population in the defense against viruses. pDCs detect viral pathogen associated molecular patterns (PAMPs) through pattern recognition receptors (PRR). PRR/PAMP interactions trigger signaling events that induce interferon (IFN) production to initiate local and systemic responses. pDCs produce Type I and Type III (IFNL) IFNs in response to HCV RNA. Extracellular HCV core protein (Core) is found in the circulation in chronic infection. This study defined how Core modulates PRR signaling in pDCs. Type I and III IFN expression and production following exposure to recombinant Core or β-galactosiade was assessed in human GEN2.2 cells, a pDC cell line. Core suppressed type I and III IFN production in response to TLR agonists and the HCV PAMP agonist of RIG-I. Core suppression of IFN induction was linked with decreased IRF-7 protein levels and increased non-phosphorylated STAT1 protein. Circulating Core protein interferes with PRR signaling by pDCs to suppress IFN production. Strategies to define and target Core effects on pDCs may serve to enhance IFN production and antiviral actions against HCV.
Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America; Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
Amy E L
AE
Stone
Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America; Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
Angela
A
Mitchell
Department of Global Health, University of Washington, Seattle, Washington, United States of America.
Jessica
J
Brownell
Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
Daniel J
DJ
Miklin
Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America; Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
Lucy
L
Golden-Mason
Department of Global Health, University of Washington, Seattle, Washington, United States of America; Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America.
Stephen J
SJ
Polyak
Department of Immunology, University of Washington, Seattle, Washington, United States of America.
Michael J
MJ
Gale
Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America; Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America; Denver Veteran's Affairs Medical Center, Denver, Colorado, United States of America.
Hugo R
HR
Rosen
D016923:Cell Death; D002460:Cell Line; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000378:metabolism*; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism*; D007372:Interferons / Q000096:biosynthesis*; D008954:Models, Biological; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism; D014758:Viral Core Proteins / Q000378:metabolism* / Q000494:pharmacology
D050839:Interferon Regulatory Factor-7; D050794:STAT1 Transcription Factor; D051193:Toll-Like Receptors; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D007372:Interferons