Abstract
Persistent infections with hepatitis C virus (HCV) may result in life-threatening liver disease, including cirrhosis and cancer, and impose an important burden on human health. Understanding how the virus is capable of achieving persistence in the majority of those infected is thus an important goal. Although HCV has evolved multiple mechanisms to disrupt and block cellular signaling pathways involved in the induction of interferon (IFN) responses, IFN-stimulated gene (ISG) expression is typically prominent in the HCV-infected liver. Here, we show that Toll-like receptor 3 (TLR3) expressed within uninfected hepatocytes is capable of sensing infection in adjacent cells, initiating a local antiviral response that partially restricts HCV replication. We demonstrate that this is dependent upon the expression of class A scavenger receptor type 1 (MSR1). MSR1 binds extracellular dsRNA, mediating its endocytosis and transport toward the endosome where it is engaged by TLR3, thereby triggering IFN responses in both infected and uninfected cells. RNAi-mediated knockdown of MSR1 expression blocks TLR3 sensing of HCV in infected hepatocyte cultures, leading to increased cellular permissiveness to virus infection. Exogenous expression of Myc-MSR1 restores TLR3 signaling in MSR1-depleted cells with subsequent induction of an antiviral state. A series of conserved basic residues within the carboxy-terminus of the collagen superfamily domain of MSR1 are required for binding and transport of dsRNA, and likely facilitate acidification-dependent release of dsRNA at the site of TLR3 expression in the endosome. Our findings reveal MSR1 to be a critical component of a TLR3-mediated pattern recognition receptor response that exerts an antiviral state in both infected and uninfected hepatocytes, thereby limiting the impact of HCV proteins that disrupt IFN signaling in infected cells and restricting the spread of HCV within the liver.
Highlights
Hepatitis C virus (HCV) is an hepatotropic, positive-strand RNA virus classified within the Flaviviridae family [1]
Persistent hepatitis C virus (HCV) infection is an important cause of fatal cirrhosis and liver cancer in humans
We show here that this is due, at least in part, to Tolllike receptor 3 sensing of HCV mediated by class A scavenger receptor type 1 (MSR1)-dependent endocytosis and transport of extracellular viral double-stranded RNA allowing it to be engaged by Toll-like receptor 3 (TLR3) in the late endosome
Summary
Hepatitis C virus (HCV) is an hepatotropic, positive-strand RNA virus classified within the Flaviviridae family [1]. It is an important human pathogen since most individuals fail to eliminate the virus when first infected This results in persistent infection and a chronic inflammatory state within the liver that leads over time to clinically significant complications including progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma. NS5B is an RNAdependent RNA polymerase and the catalytic core of a large macromolecular, membrane-bound replicase complex that directs replication of the viral RNA, producing double-stranded RNA (dsRNA) replication intermediates as well as new viral genomes These viral RNAs are recognized as pathogen-associated molecular patterns (PAMPs) by innate immune sensors in host cells, but exactly which sequences and how these RNAs are sensed remains only partly elucidated [2]
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