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UNLABELLED: 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. CONCLUSION: 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.

Original publication

DOI

10.1002/hep.26911

Type

Journal article

Journal

Hepatology

Publication Date

04/2014

Volume

59

Pages

1320 - 1330

Keywords

Carcinoma, Hepatocellular, Cell Line, Tumor, Cell Polarity, Hep G2 Cells, Hepacivirus, Hepatitis C, Humans, Immunity, Innate, Interleukin-1beta, Liver Neoplasms, Macrophage Activation, Macrophages, Occludin, Tetraspanin 28, Tight Junctions, Tumor Necrosis Factor-alpha, Virus Internalization