Abstract
Preventing virally induced liver disease begins with an understanding of the host factors that define susceptibility to infection. Hepatitis C virus (HCV) is a global health issue, with an estimated 170 million infected individuals at risk of developing liver disease including fibrosis and hepatocellular carcinoma. The liver is the major reservoir supporting HCV replication and this hepatocellular tropism is defined by HCV engagement of cellular entry receptors. Hepatocytes are polarized in vivo and this barrier function limits HCV entry. We previously reported that activated macrophages promote HCV entry into polarized hepatocytes via a TNF-α-dependent process; however, the underlying mechanism was not defined. In this study, we show that several TNF superfamily members, including TNF-α, TNF-β, TWEAK and LIGHT, promote HCV entry via NF-κB-mediated activation of myosin light chain kinase (MLCK) and disruption of tight junctions. These observations support a model where HCV hijacks an inflammatory immune response to stimulate infection and uncovers a role for NF-κB-MLCK signalling in maintaining hepatocellular tight junctions.
Highlights
Hepatitis C virus (HCV) is a global health issue with an estimated 170 million infected individuals worldwide
To investigate the potential for other TNF superfamily members to promote hepatocellular permissiveness to support HCV entry, we screened a panel of recombinant human TNF superfamily members for their effect on HCV pseudoparticle (HCVpp) infection of polarized HepG2.CD81 cells (Fig. 1a)
In addition to TNF-a, we found that TNF-b, TWEAK and LIGHT promote HCVpp infection in a dose-dependent manner (Fig. 1b)
Summary
Hepatitis C virus (HCV) is a global health issue with an estimated 170 million infected individuals worldwide. Infection is initiated by the viral encoded E1E2 glycoproteins interacting with cellular receptors: tetraspanin CD81, scavenger receptor BI (SR-BI), epidermal growth factor receptor, the cholesterol absorption regulator Niemann– Pick disease type C1-like 1 protein, and tight junction proteins claudin-1 and occludin (reviewed in [1, 2]). This multi-step process of receptor engagement primes a clathrin-dependent endocytic uptake of particles into the liver. Hepatocytes are polarized and HCV particles entering the liver encounter their basolateral surface that expresses the ‘viral attachment’ proteins CD81 and SR-BI [3]. Occludin localizes almost exclusively to the apical tight junctions, which are considered inaccessible to virus particles, raising questions on its role in the viral internalization process [5, 6]
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