Project description:Previous studies have paid more attention to hepatitis B e antigen (HBeAg) intrauterine exposure, however the effect of solely hepatitis B surface antigen (HBsAg) exposure on the immune response of offspring against hepatitis B virus (HBV) is still unclear. In this study, we investigated whether HBsAg intrauterine exposure affected the offspring's immune response against HBV and the relevant mechanism, which is important for the prevention of HBV mother-to-infant transmission.
Project description:Hepatitis B virus (HBV) can integrate into the chromosomes of infected hepatocytes, contributing to the production of hepatitis B surface antigen (HBsAg) and to hepatocarcinogenesis. We performed spatial transcriptomics to investigate the intrahepatic cell heterogeneity and the spatial distribution of transcriptionally active HBV integration events in different phases of chronic HBV infection. Our analysis revealed that transcriptionally active HBV integration occurred in chronically HBV-infected patients in different phases, including those patients with HBsAg loss, and antiviral treatment was associated with a decreased number and extent of viral integrations.
Project description:Hepatitis B surface antigen (HBsAg) secretion may impact the immune response in chronic hepatitis B virus (HBV) infection. Therapeutic approaches to suppress HBsAg production are being investigated. Our study aims to examine the immunomodulatory effects of high and low levels of circulating HBsAg by analyzing single-cell RNA sequencing data (scRNAseq) from blood and liver fine-needle aspirates (FNA). This will help to better understand anti-HBV immunity.
Project description:In the current single-armed prospective study, HBeAg negative chronic hepatitis B patients with compensated liver function undertook weekly PEG-IFN subcutaneous injection for 48 weeks. Furthermore, serum miRNAs, extracted from sera taken at 24th week, were analyzed to identify predictive biomarkers for HBsAg reduction.
Project description:Background: Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection—immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases—remains unexplored. </p> Methods: To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels. </p> Results: Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate–NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase. </p> Conclusions: The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate–NADH shuttle. </p> The Lipid assays and the Biogenic amine and Acyl-carnitine assays for this study can be found in the MetaboLights studies MTBLS279 and MTBLS280 respectively.
Project description:Background: Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection—immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases—remains unexplored. </p> Methods: To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels. </p> Results: Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate–NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase. </p> Conclusions: The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate–NADH shuttle. </p> The Oxylipin assay and the Biogenic amine and Acyl-carnitine assays for this study can be found in the MetaboLights studies MTBLS253 and MTBLS280 respectively.
Project description:Chronic HBV is clinically categorized into 4 phases by a combination of serum HBV DNA levels, HBeAg status and alanine aminotransferase (ALT): immunotolerant (IT), immune-active (IA), inactive carrier (IC) and HBeAg-negative hepatitis (ENEG). Immune and virological measurements in the blood have proven useful but are insufficient to explain the interrelation between the immune system and the virus since immune dynamics differ in the blood and liver. Furthermore, the inflammatory response in the liver and parenchymal cells cannot be fully captured in blood.
Project description:Background: Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection—immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases—remains unexplored. </p> Methods: To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels. </p> Results: Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate–NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase. </p> Conclusions: The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate–NADH shuttle. </p> The Oxylipin assay and the Lipid assays for this study can be found in the MetaboLights studies MTBLS253 and MTBLS279 respectively.
Project description:BACKGROUND: Hepatocellular carcinoma (HCC) is a common complication of chronic viral hepatitis. In support of this notion, we have reported that hepatitis B surface antigen (HBsAg)-specific CD8+ T lymphocytes critically contribute to inducing chronic liver cell injury that exerts high carcinogenic potential in a hepatitis B virus (HBV) Tg mouse model. The dynamics of the molecular signatures responsible for hepatocellular carcinogenesis are not fully understood. The current study was designed to determine the serial changes in gene expression profiles in a model of chronic immune-mediated hepatitis. METHODS: Three-month-old HBV Tg mice were immunologically reconstituted with bone marrow cells and splenocytes from syngeneic nonTg donors. Liver tissues were obtained every three months until 18 months at which time all mice developed multiple liver tumors. Nitrative DNA lesions and hepatocyte turnover were assessed immunohistochemically. Gene expression profiles were generated by extracting total RNA from the tissues and analyzing by microarray. RESULTS: The nitrative DNA lesions and the regenerative proliferation of hepatocytes were increased during the progression of chronic liver disease. In a gene expression profile analysis of liver samples, the chemokine- and T cell receptor (TCR)-mediated pathways were enhanced during chronic hepatitis, and the EGF- and VEGF-mediated pathways were induced in HCC. Among these molecules, the protein levels of STAT3 were greatly enhanced in all hepatocyte nuclei and further elevated in the cytoplasm in HCC tissue samples at 18 months, and the levels of phosphorylated TP53 (p-p53-Ser 6 and -Ser 15) were increased in liver tissues. CONCLUSIONS: HBV-specific immune responses caused unique molecular signatures in the liver tissues of chronic hepatitis and triggered subsequent carcinogenic gene expression profiles in a mouse model. The results suggest a plausible molecular basis responsible for HBV-induced immune pathogenesis of HCC.
Project description:The underlying mechanism of chronic hepatitis B virus (HBV) functional cure by interferon (IFN), especially in patients with low HBsAg or/and young ages, is still unresolved for lacking surrogate models. Here, we generated a type I interferon receptor humanized mouse (huIFNAR mouse) through a CRISPR/Cas9-based knock-in strategy. Then, we demonstrated that human IFN stimulated a similar gene expression profile of huIFNAR peripheral blood mononuclear cells (PBMC) to what in human PBMCs, supporting the representativeness of the novel mouse model in functionally analyzing human IFN in vivo. Next, we revealed a markedly tissue-specific gene expression atlas against human IFN treatment in the multiple organs less appreciated in healthy humans in vivo. Finally, using the AAV-HBV model, we test the antiviral effects of human interferon in this mouse. Fifteen-week human PEG-IFNα2 treatment significantly reduced HBsAg and HBeAg and even achieved HBsAg seroconversion. We observed that activation of intrahepatic monocytes and effector memory CD8 T cells by human interferon might be critical for HBsAg suppression. In conclusion, our novel huIFNAR mouse can authentically respond to human Interferon stimulation, providing a novel platform to study interferon function in vivo. The PEG-IFNα2 treatment successfully suppresses intrahepatic HBV replication and achieved HBsAg seroconversion in some mice.