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.