title: Activated macrophages promote hepatitis C virus entry in a tumor necrosis factor-dependent manner.
abstract: Macrophages are critical components of the innate immune response in the liver. Chronic hepatitis C is associated with immune infiltration and the infected liver shows a significant increase in total macrophage numbers; however, their role in the viral life cycle is poorly understood. Activation of blood-derived and intrahepatic macrophages with a panel of Toll-like receptor agonists induce soluble mediators that promote hepatitis C virus (HCV) entry into polarized hepatoma cells. We identified tumor necrosis factor α (TNF-α) as the major cytokine involved in this process. Importantly, this effect was not limited to HCV; TNF-α increased the permissivity of hepatoma cells to infection by Lassa, measles and vesicular stomatitis pseudoviruses. TNF-α induced a relocalization of tight junction protein occludin and increased the lateral diffusion speed of HCV receptor tetraspanin CD81 in polarized HepG2 cells, providing a mechanism for their increased permissivity to support HCV entry. High concentrations of HCV particles could stimulate macrophages to express TNF-α, providing a direct mechanism for the virus to promote infection.
  
  
  CONCLUSIONS
  This study shows a new role for TNF-α to increase virus entry and highlights the potential for HCV to exploit existing innate immune responses in the liver to promote de novo infection events.
authors.affiliation: Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: Nicola F
authors.initials: NF
authors.lastname: Fletcher
authors.forename: Rupesh
authors.initials: R
authors.lastname: Sutaria
authors.forename: Juandy
authors.initials: J
authors.lastname: Jo
authors.forename: Amy
authors.initials: A
authors.lastname: Barnes
authors.forename: Miroslava
authors.initials: M
authors.lastname: Blahova
authors.forename: Luke W
authors.initials: LW
authors.lastname: Meredith
authors.forename: Francois-Loic
authors.initials: FL
authors.lastname: Cosset
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Curbishley
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000502:physiology; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D062793:Occludin / Q000378:metabolism; D060225:Tetraspanin 28 / Q000378:metabolism; D019108:Tight Junctions / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D053586:Virus Internalization
chemical_list: D053583:Interleukin-1beta; D062793:Occludin; D060225:Tetraspanin 28; D014409:Tumor Necrosis Factor-alpha