scholarly journals Manganese Breaks the Immune Tolerance of HBs-Ag

2021 ◽  
Vol 8 (2) ◽  
Author(s):  
Mengxin Lin ◽  
Ruyi Guo ◽  
Cuiping Ma ◽  
Dawu Zeng ◽  
Zhijun Su
Keyword(s):  
Alanine Aminotransferase ◽  
Serum Levels ◽  
Hbv Infection ◽  
Type I ◽  
Lymphocyte Infiltration ◽  
Adeno Associated Virus ◽  
B Virus ◽  
Mouse Hepatocytes ◽  
Hbs Ag ◽  
Alt Activity

Abstract Background Manganese (Mn2+) has been shown to promote type I interferon (IFN) production and activate the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) signaling pathway, suggesting that Mn2+ could be used as an adjuvant for vaccination. Methods In present study, the effects of Mn2+ on vaccination against hepatitis B virus (HBV) were evaluated. We treated mouse hepatocytes and kuppfer cells with Mn2+ with or without adeno-associated virus (AAV)–HBV infection. Expression of IFN-α and IFN-β and activation of TBK1 and IRF3 were monitored. Wild-type and STING-/- mice were treated with Mn2+ and then infected with AAV-HBV. Serum levels of HBV surface antigen (HBsAg), alanine aminotransferase (ALT) activity, IFN-α, and IFN-β were detected. Lymphocyte infiltration in the liver was evaluated. HBsAg-Tg mice were vaccinated with Mn2+ and HBsAg. The serum levels of HBsAg antibody, alanine transaminase activity, and IFN-β were monitored after vaccination. Results Mn2+ promoted IFN-α and IFN-β production in mouse hepatocytes and kuppfer cells. Mn2+ failed to promote IFN-α and IFN-β production in kuppfer cells deficient in STING. Mn2+ promoted activation/phosphorylation of TBK1 and IRF3 during AAV-HBV infection. Mn2+ decreased serum levels of HBsAG, increased serum levels of alanine aminotransferase (ALT), IFN-α and IFN-β, and enhanced lymphocyte infiltration and the percentage of IFN-γ-producing CD8+ T cells in the liver of AAV-HBV-infected mice. In contrast, Mn2+ treatment did not affect serum levels of HBsAG, ALT, IFN-α, or IFN-β in STING-deficient mice. Conclusions Mn2+ promoted HBsAG antibody, ALT, and IFN-β production after HBsAG immunization. Mn2+ promoted type I IFN production in AAV-HBV infection and HBsAG immunization and could be used as an adjuvant for vaccination.

scholarly journals Dissociation of alanine aminotransferase values in acute hepatitis A patients with and without past experience to the hepatitis B virus

1991 ◽  
Vol 106 (2) ◽  
pp. 397-402 ◽  
Author(s):  
A. A. Papachristou ◽  
A. S. Dumas ◽  
V. C. Katsouyannopoulos
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Acute Hepatitis ◽  
Alanine Aminotransferase ◽  
Hepatitis A ◽  
Hbv Infection ◽  
Previous Experience ◽  
B Virus ◽  
Acute Hepatitis A ◽  
Acute Hepatitis B

SUMMARYSerological markers and peak serum alanine aminotransferase (ALT) values of 140 in-patients with acute hepatitis, either type A (n= 90), or type B (n= 50) were prospectively assessed. In 23 out of the 90 patients with acute hepatitis A, evidence of previous experience with hepatitis B virus (HBV) was found, whereas 35 out of the 50 patients with acute hepatitis B had past contact with hepatitis A virus (HAV). The mean peak ALT values [S.D.] were significantly higher in hepatitis A patients with previous experience with HBV (1413 [704] i.u./l), when compared to those without such experience (842 [464] i.u./l, P < 0·001). Such a difference was not evident between acute hepatitis B patients, whether or not they had previous contact with HAV. We conclude that when acute hepatitis A is superimposed on past HBV infection an augmented transaminaemia, indicative of enhanced liver cell necrosis, takes place although a definite explanation is lacking. We suggest that individuals with markers of HBV infection should be early candidates for HAV immunization.

scholarly journals Hepatitis B Virus Infection of a Mouse Hepatic Cell Line Reconstituted with Human Sodium Taurocholate Cotransporting Polypeptide

2016 ◽  
Vol 90 (9) ◽  
pp. 4827-4831 ◽  
Author(s):  
Florian A. Lempp ◽  
Bingqian Qu ◽  
Yong-Xiang Wang ◽  
Stephan Urban
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Line ◽  
Sodium Taurocholate ◽  
Hbv Infection ◽  
Hepatitis B Virus Infection ◽  
Hepatic Cells ◽  
Mouse Liver Cell ◽  
B Virus ◽  
Mouse Hepatocytes

Hepatitis B virus (HBV) enters hepatocytes via its receptor, human sodium taurocholate cotransporting polypeptide (hNTCP). So far, HBV infection has been achieved only in human hepatic cells reconstituted with hNTCP and not in cells of mouse origin. Here, the first mouse liver cell line (AML12) which gains susceptibility to HBV upon hNTCP expression is described. Thus, HBV infection of receptor-expressing mouse hepatocytes does not principally require a human cofactor but can be triggered by endogenous murine determinants.

scholarly journals Animal Models of Hepatitis B Virus Infection–Success, Challenges, and Future Directions

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 777
Author(s):  
Yongzhen Liu ◽  
Stephanie Maya ◽  
Alexander Ploss
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Animal Models ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Hbv Infection ◽  
Type I ◽  
Future Directions ◽  
Chronic Hepatitis B Virus ◽  
B Virus

Chronic hepatitis B virus (HBV) infection affects more than 250 million people worldwide, which greatly increases the risk for terminal liver diseases, such as liver cirrhosis and hepatocellular carcinoma (HCC). Even though current approved antiviral therapies, including pegylated type I interferon (IFN) and nucleos(t)ide analogs, can effectively suppress viremia, HBV infection is rarely cured. Since HBV exhibits a narrow species tropism and robustly infects only humans and higher primates, progress in HBV research and preclinical testing of antiviral drugs has been hampered by the scarcity of suitable animal models. Fortunately, a series of surrogate animal models have been developed for the study of HBV. An increased understanding of the barriers towards interspecies transmission has aided in the development of human chimeric mice and has greatly paved the way for HBV research in vivo, and for evaluating potential therapies of chronic hepatitis B. In this review, we summarize the currently available animal models for research of HBV and HBV-related hepadnaviruses, and we discuss challenges and future directions for improvement.

scholarly journals STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus

2014 ◽  
Vol 59 (2) ◽  
pp. 1273-1281 ◽  
Author(s):  
Fang Guo ◽  
Yanxing Han ◽  
Xuesen Zhao ◽  
Jianghua Wang ◽  
Fei Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cytokine Response ◽  
Hbv Infection ◽  
Stable Cell Line ◽  
Type I ◽  
Antiviral Immune Response ◽  
Hbv Replication ◽  
B Virus

ABSTRACTChronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted.

Antiviral Therapy in Hepatitis B Virus-Associated Liver Cirrhosis

2015 ◽  
Vol 33 (4) ◽  
pp. 608-612 ◽  
Author(s):  
Tobias Boettler ◽  
Robert Thimme
Keyword(s):  
Liver Cirrhosis ◽  
Hepatitis B Virus ◽  
Liver Fibrosis ◽  
Hepatitis B ◽  
Antiviral Therapy ◽  
Hbv Infection ◽  
Hepatic Decompensation ◽  
Chronic Hepatitis B Virus ◽  
B Virus ◽  
Hbs Ag

Background: Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of liver cirrhosis and hepatocellular carcinoma (HCC). Key Messages: In patients with advanced liver fibrosis or liver cirrhosis, antiviral therapy is mandatory to slow down, halt or reverse disease progression and possibly reduce the risk of HCC development. As in patients without advanced fibrosis, PEG-interferon and nucleoside/nucleotide analogues (NUCs) are available for antiviral therapy. NUC therapy should be performed indefinitely as the rates of HBs-Ag loss are low. Entecavir or tenofovir should be preferred due to their strong antiviral potency and their high barrier to resistance. PEG-interferon therapy can be administered to patients with compensated liver disease but should not be offered to patients with signs of hepatic decompensation. Conclusions: Antiviral therapy in chronic HBV infection can reduce liver fibrosis and even revert overt cirrhosis. Whether it also reduces the risk of HCC development in cirrhotic patients remains elusive and might vary in different countries and ethnicities.

scholarly journals Review of Lambda Interferons in Hepatitis B Virus Infection: Outcomes and Therapeutic Strategies

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1090
Author(s):  
Laura A. Novotny ◽  
John Grayson Evans ◽  
Lishan Su ◽  
Haitao Guo ◽  
Eric G. Meissner
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Reverse Transcriptase ◽  
Hbv Infection ◽  
Type I Interferons ◽  
Type I ◽  
Reverse Transcriptase Inhibitors ◽  
Chronic Hbv Infection ◽  
B Virus ◽  
Chronic Hbv

Hepatitis B virus (HBV) chronically infects over 250 million people worldwide and causes nearly 1 million deaths per year due to cirrhosis and liver cancer. Approved treatments for chronic infection include injectable type-I interferons and nucleos(t)ide reverse transcriptase inhibitors. A small minority of patients achieve seroclearance after treatment with type-I interferons, defined as sustained absence of detectable HBV DNA and surface antigen (HBsAg) antigenemia. However, type-I interferons cause significant side effects, are costly, must be administered for months, and most patients have viral rebound or non-response. Nucleos(t)ide reverse transcriptase inhibitors reduce HBV viral load and improve liver-related outcomes, but do not lower HBsAg levels or impart seroclearance. Thus, new therapeutics are urgently needed. Lambda interferons (IFNLs) have been tested as an alternative strategy to stimulate host antiviral pathways to treat HBV infection. IFNLs comprise an evolutionarily conserved innate immune pathway and have cell-type specific activity on hepatocytes, other epithelial cells found at mucosal surfaces, and some immune cells due to restricted cellular expression of the IFNL receptor. This article will review work that examined expression of IFNLs during acute and chronic HBV infection, the impact of IFNLs on HBV replication in vitro and in vivo, the association of polymorphisms in IFNL genes with clinical outcomes, and the therapeutic evaluation of IFNLs for the treatment of chronic HBV infection.

Prevention of Perinatal Acquisition of Hepatitis B Virus Carriage Using Vaccine: Preliminary Report of a Randomized, Double-Blind Placebo-Controlled and Comparative Trial

PEDIATRICS ◽  
1985 ◽  
Vol 76 (5) ◽  
pp. 713-718 ◽  
Author(s):  
Zhi-Yi Xu ◽  
Chung-Bo Liu ◽  
Donald P. Francis ◽  
Robert H. Purcell ◽  
Zhi-Li Gun ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Vaccine Efficacy ◽  
Controlled Trial ◽  
Hepatitis B Vaccine ◽  
Hbv Infection ◽  
Double Blind ◽  
Double Blind Placebo ◽  
B Virus ◽  
Hbs Ag

Hepatitis B is a serious disease of global significance. In developing countries, hepatitis B virus (HBV) infection and its sequelae rank among the public health problems of highest priority. Infants born to mothers who are chronic carriers of HBV are at particularly high risk of acquiring infection and becoming chronic HBV carriers. The efficacy of hepatitis B vaccine alone in preventing the transmission of HBV to infants born to HBV carrier mothers was determined in a double-blind placebo-controlled trial. Infants received plasma-derived vaccine at birth, 1 month, and 6 months of age. Of 180 infants born to hepatitis B surface antigen (HBs Ag)-positive mothers, equal numbers received National Institute of Allergy and Infectious Disease (NIAID) vaccine, Beijing Institute of Vaccine and Serum (BIVS) vaccine, and placebo. The cumulative seroconversion to the vaccines at 1 year of age was 95% and 75%, respectively. Vaccine efficacy as measured by the prevention of HBs Ag-positive events was 88% for the NIAID vaccine and 51% for the BIVS vaccine. Vaccine efficacy was similar among infants born to hepatitis Be antigen-positive mothers. Because of the low efficacy of the BIVS vaccine, an additional group of 28 infants was given vaccine and hepatitis B immune globulin at birth. The resulting efficacy was 83%. The results of this trial indicate that hepatitis B vaccine alone can substantially reduce perinatally acquired HBV infection and the resulting chronic carrier state.

scholarly journals Activation of Stimulator of Interferon Genes in Hepatocytes Suppresses the Replication of Hepatitis B Virus

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Fang Guo ◽  
Liudi Tang ◽  
Sainan Shu ◽  
Mohit Sehgal ◽  
Muhammad Sheraz ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatoma Cells ◽  
Innate Immune ◽  
Hbv Infection ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Hbv Replication ◽  
B Virus ◽  
Mouse Hepatocytes

ABSTRACT Induction of interferon and proinflammatory cytokines is a hallmark of the infection of many different viruses. However, hepatitis B virus (HBV) does not elicit a detectable cytokine response in infected hepatocytes. In order to investigate the molecular mechanism underlying the innate immune evasion, a functional cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway was reconstituted in a human hepatoma cell line supporting tetracycline-inducible HBV replication. It was demonstrated that induction of HBV replication neither activated nor inhibited this cytosolic DNA sensing pathway. However, human hepatoma cells, as well as immortalized mouse hepatocytes, express low levels of STING, which upon activation by cGAMP, the natural ligand of STING, led to induction of a proinflammatory cytokine response. Treatment of immortalized mouse hepatocytes supporting HBV replication with either cGAMP or a small molecule pharmacologic STING agonist significantly reduced viral DNA in a STING- and Janus kinase 1-dependent manner. Moreover, cGAMP treatment was able to induce inflammatory cytokine gene expression and inhibit the transcription of covalently closed circular DNA in HBV-infected human hepatoma cells expressing sodium taurocholate cotransporting polypeptide, an essential receptor for HBV infection of hepatocytes. The studies reported here and previously (F. Guo et al., Antimicrob Agents Chemother 59:1273–1281, 2015, https://doi.org/10.1128/AAC.04321-14 ) thus support the notion that pharmacological activation of STING in macrophages and hepatocytes induces host innate responses that can efficiently control HBV replication. Hence, despite not playing a significant role in host innate immune response to HBV infection of hepatocytes, STING is potentially a valuable target for immunotherapy of chronic hepatitis B.

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