Activated macrophages promote hepatitis C virus entry in a tumor necrosis factor-dependent manner
Research output: Contribution to journal › Article › peer-review
Authors
Colleges, School and Institutes
External organisations
- Viral Hepatitis Laboratory; Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*STAR); Singapore
- Université de Lyon; Lyon France
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. 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. (Hepatology 2014;59:1320-1330)
Details
Original language | English |
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Pages (from-to) | 1320-1330 |
Journal | Hepatology |
Volume | 59 |
Issue number | 4 |
Early online date | 25 Feb 2014 |
Publication status | Published - 1 Apr 2014 |