Activated macrophages promote hepatitis C virus entry in a tumor necrosis factor‐dependent manner. Issue 4 (25th February 2014)

• Record Type: Journal Article
• Authors: Fletcher, Nicola F.; Sutaria, Rupesh; Jo, Juandy; Barnes, Amy; Blahova, Miroslava; Meredith, Luke W.; Cosset, Francois‐Loic; Curbishley, Stuart M.; Adams, David H.; Bertoletti, Antonio; McKeating, Jane A.
• Is Part Of: Hepatology. Volume 59:Issue 4(2014:Apr.)
• Page Start: 1320
• Page End: 1330
• Publication Date: 2014-02-25
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.26911
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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. <italic>Conclusion</italic>: 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 <italic>de novo</italic> infection events. (H<sc>epatology</sc> 2014;59:1320‐1330)</p> </abstract>