Hepatitis B Virus and DNA Stimulation Trigger a Rapid Innate Immune Response through NF-κB.
Cell-intrinsic innate immunity provides a rapid first line of defense to thwart invading viral pathogens through the production of antiviral and inflammatory genes. However, the presence of many of these signaling pathways in the liver and their role in hepatitis B virus (HBV) pathogenesis is unknown. Recent identification of intracellular DNA-sensing pathways and involvement in numerous diverse disease processes including viral pathogenesis and carcinogenesis suggest a role for these processes in HBV infection. To characterize HBV-intrinsic innate immune responses and the role of DNA- and RNA-sensing pathways in the liver, we used in vivo and in vitro models including analysis of gene expression in liver biopsies from HBV-infected patients. In addition, mRNA and protein expression were measured in HBV-stimulated and DNA-treated hepatoma cell lines and primary human hepatocytes. In this article, we report that HBV and foreign DNA stimulation results in innate immune responses characterized by the production of inflammatory chemokines in hepatocytes. Analysis of liver biopsies from HBV-infected patients supported a correlation among hepatic expression of specific chemokines. In addition, HBV elicits a much broader range of gene expression alterations. The induction of chemokines, including CXCL10, is mediated by melanoma differentiation-associated gene 5 and NF-κB-dependent pathways after HBV stimulation. In conclusion, HBV-stimulated pathways predominantly activate an inflammatory response that would promote the development of hepatitis. Understanding the mechanism underlying these virus-host interactions may provide new strategies to trigger noncytopathic clearance of covalently closed circular DNA to ultimately cure patients with HBV infection.
Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, FL 33136; Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136;
Masato
M
Yoneda
Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136; and.
Jinhee
0000-0003-2823-1225
J
Hyun
Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136; and.
Silvia
S
Jakubski
Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 226-0004, Japan.
Satoru
0000-0002-5666-5218
S
Saito
Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 226-0004, Japan.
Atsushi
0000-0002-6263-1436
A
Nakajima
Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, FL 33136; Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136;
Eugene R
0000-0002-0978-2040
ER
Schiff
Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, FL 33136; Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136; Ethomas1@med.miami.edu.
Emmanuel
E
Thomas
D004279:DNA, Viral / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006509:Hepatitis B / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction
D004279:DNA, Viral; D016328:NF-kappa B