title: Hepatitis C virus impairs natural killer cell-mediated augmentation of complement synthesis.
abstract: Natural killer (NK) cells and the complement system play critical roles in the first line of defense against pathogens. The synthesis of complement components C4 and C3 is transcriptionally downregulated by hepatitis C virus (HCV) core and NS5A proteins, and this negative regulation is apparent in chronically HCV-infected patients. In this study, we have examined the potential contribution of an NK cell line as a model in regulating complement synthesis. Coculture of NK cells (NK3.3) with human hepatoma cells (Huh7.5) expressing HCV core or NS5A protein led to a significant increase in C4 and C3 complement synthesis via enhanced specific transcription factors. Reestablishment of complement protein expression was found to be mediated by direct interaction between NKG2D on NK cells and the hepatocyte protein major histocompatibility complex class I-related chains A and B (MICA/B) and not to be associated with specific cytokine signaling events. On the other hand, C4 and C3 synthesis remained impaired in a coculture of NK cells and Huh7.5 cells infected with cell culture-grown HCV. The association between these two cell types through NKG2D and MICA/B was examined further, with MICA/B expression in HCV-infected hepatocytes found to remain inhibited during coculture. Further experiments revealed that the HCV NS2 and NS5B proteins are responsible for the HCV-associated decrease in MICA/B. These results suggest that HCV disables a key receptor ligand in infected hepatoma cells, thereby inhibiting the ability of infected cells to respond to stimuli from NK cells to positively regulate complement synthesis.
  
  
  OBJECTIVE
  The complement system contributes to the protection of the host from virus infection. However, the involvement of complement in viral hepatitis has not been well documented. Whether NK cells affect complement component expression in HCV-infected hepatocytes remains unknown. Here, we have shown how HCV subverts the ability of NK cells to positively mediate complement protein expression.
authors.affiliation: Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA.
authors.forename: Hangeun
authors.initials: H
authors.lastname: Kim
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Bose
authors.forename: Keith
authors.initials: K
authors.lastname: Meyer
authors.forename: Ranjit
authors.initials: R
authors.lastname: Ray
mesh_terms: D002460:Cell Line; D003176:Complement C3 / Q000096:biosynthesis / Q000235:genetics; D003181:Complement C4 / Q000096:biosynthesis / Q000235:genetics; D003165:Complement System Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008213:Lymphocyte Activation / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D011485:Protein Binding; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D003176:Complement C3; D003181:Complement C4; D003165:Complement System Proteins; D015395:Histocompatibility Antigens Class I; D055655:NK Cell Lectin-Like Receptor Subfamily K; D017361:Viral Nonstructural Proteins; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; C097010:NS2 protein, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase