TNF superfamily members promote hepatitis C virus entry via an NF-κB and myosin light chain kinase dependent pathway

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.

Bacterial flagellin promotes viral entry via an NF-kB and Toll Like Receptor 5 dependent pathway

“…5b). MLN-4924 inhibits the Nedd8-activating enzyme that regulates Cullin-RING ubiquitin ligases 27 and has been reported to limit NF-ΚB signalling pathways 28,29 therefore we evaluated its effect on flagellin induced NF-ΚB signaling. We confirmed that MLN4924 inhibits STm-dependent NF-ΚB activation 16 (Fig.…”

“…We noted a temperature-dependent effect of flagellin to augment VSV-Gpp cell-association that may reflect a requirement for active receptor diffusion at the plasma membrane. Of note, we previously reported a role for tumor necrosis factor and related family members to induced NF-ΚB signaling to regulate the lateral diffusion of host tetraspanin CD81 via cytoplasmic tail association with the actin cytoskeleton 33,34 , providing a mechanism for flagellin to regulate membrane protein dynamics. The ability of flagellin to promote MeV encoded glycoprotein-SLAMF1 cell-cell plasma membrane fusion lends further support to a model where flagellin signalling is effective at the plasma membrane and does not require vesicular trafficking or endocytosis.…”

MicroRNA-1 Negatively Regulates Peripheral NK Cell Function via Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Signaling Pathways During PPRV Infection

“…Further analysis showed that functional activity of NK cells was negatively associated with the expression levels TWEAK. The importance of TWEAK is emphasized by the fact that some viruses, including human HCV and KSHV, can increase the constitutive levels of TWEAK to facilitate their infections (42,43). Furthermore, studies in humans and mice have demonstrated that TWEAK can prevent local cytotoxicity and counterbalance the cytotoxic function of NK cells during the early phase of infection (44)(45)(46).…”

Application of Impedance-Based Techniques in Hepatology Research

“…One challenge to studying hepatitis B and C infection and antiviral therapeutics in vitro is the inability to transfect most cell lines with viruses. Two commonly used hepatic cell lines, Huh-7 and HepaRGs, have both been used extensively in the study of hepatitis B and C [28][29][30][31][32][33][34]. Huh-7 cells, established in 1982 from a human hepatocellular carcinoma [35], are known to produce the human plasma proteins albumin, transferrin, alpha fetoprotein and fibronectin [36].…”