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)
Highlights
Macrophages are critical components of the innate immune response in the liver
IL-4 or tumor necrosis factor (TNF)-a/IFN-c stimulated macrophage conditioned medium (CM) had no effect on HCV pseudoparticle (HCVpp) infectivity (Fig. 1A)
Macrophages stimulated with a range of LPS concentrations (0.1-10 lg/mL) increased HCVpp infection (Fig. 1B) and this was consistent between donors
Summary
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; their role in the viral life cycle is poorly understood. Conclusion: This study shows a new role for TNF-a 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. Macrophages play an essential and early role in sensing pathogens by way of expression of Toll-like receptors (TLRs) that recognize pathogenassociated molecular patterns that prime cytokine expression, mainly interleukin (IL)21b, IL-6, and tumor necrosis factor alpha (TNF-a).[8] Kupffer cells (KCs) are the resident macrophage of the liver and in addition to early innate sensing of pathogens help to maintain the tolerogenic environment of the liver.[9] The chronic HCV-infected liver shows a significant increase in total macrophage numbers that most likely represents a local proliferation of KCs and infiltration of bone-marrow-derived monocytes[10]; their
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