Abstract
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.
Highlights
Hepatitis C Virus (HCV) is a major public health problem infecting approximately 200 million people globally [1], leading to persistence in over 80% of cases
When we examined Interferon regulatory factor (IRF)-7 and IRF-3 levels following 24 hours of protein treatment prior to 24 hours of pU/UC RNA stimulation recombinant HCV Core protein (rCore) Alters Signal Transducer and Activator of Transcription (STAT)-1 Proteins Levels Since IFN production and IRF-7 levels were decreased in rCore exposed Plasmacytoid Dendritic Cells (pDCs), we posited that this was due to decreased IFN signaling
Using published data [17,24], we calculated the amount of HCV core protein (Core) available to pDCs in HCV infected patients
Summary
Hepatitis C Virus (HCV) is a major public health problem infecting approximately 200 million people globally [1], leading to persistence in over 80% of cases. Core has been reported to modulate the immune response at multiple levels, including the innate hepatocyte response [6] and T cells through binding to gC1qR [7], the globular region of complement protein 1q receptor. Plasmacytoid dendritic cells (pDCs) are a rare population of leukocytes whose key function is to detect and respond to viruses [10]. These cells use PRRs, primarily TLRs, to detect nucleic acids from viral infections [11]. Using the GEN2.2pDC line, we found that both TLR- and RLR-mediated IFN responses were decreased by Core This effect was associated with decreased IRF-7 and increased non-phosphorylated (i.e. inactive) STAT1
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