Hepatitis B Virus and DNA Stimulation Trigger a Rapid Innate Immune Response through NF-κB

Abstract

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.

The balance of type 1 and type 2 immune responses in the contexts of hepatitis B infection and hepatitis D infection

“…These findings align with previous clinical and animal studies and with reports on HDV antigen‐stimulated Peripheral blood mononuclear cells (PBMC) Similar correlations of type 1 cytokines with HBV‐DNA in the HBV cohort and HDV‐RNA levels in the HDV cohort suggest that viral loads may play similar type 1‐stimulatory roles in the respective viral diseases (Table ). These echo previous associations with HBV viral load . The relatively scarce correlations between HBV‐DNA and cytokines in HDV further suggest that HBV viral load bears less influence on immune responses in HDV patients.…”

The Smc5/6 Complex Restricts HBV when Localized to ND10 without Inducing an Innate Immune Response and Is Counteracted by the HBV X Protein Shortly after Infection

“…These studies are also in line with the lack of elevated type I IFN levels in the serum of patients with acute HBV infection [47]. In contrast, recent in vitro studies have suggested that HBV can induce a modest IFN response in human hepatocytes [30,48–51]. However, in many of these studies the response of human hepatocytes to HBV was analyzed in the context of high levels of physiologically irrelevant cells (e.g.…”

Nucleic acid-based polymers effective against hepatitis B Virus infection in patients don’t harbor immunostimulatory properties in primary isolated liver cells

“…Antiviral activity of TLR-stimulated parenchymal and non-parenchymal human liver cells seems to be restricted to TLR3 in vitro 3435. Cytosolic pathogen recognition receptors like RIG-I, STING and cGAS can be activated in human hepatocytes as well, leading to antiviral signaling3637. However, NAP-treated PHH, KC and LSEC did not induce the expression and secretion of interferons, except KC treated with immunostimulatory REP 2006.…”