New insight in the pathobiology of hepatitis B virus infection
ABSTRACT Chronic hepatitis B virus (HBV) infection remains a major health burden and the main risk factor for the development of hepatocellular carcinoma worldwide. However, HBV is not directly cytopathic and liver injury appears to be mostly caused by repeated attempts of the host's immune responses to control the infection. Recent studies have shown that the unique replication strategy adopted by HBV enables it to survive within the infected hepatocyte while complex virus-host interplays ensure the virus is able to fulfil its replication requirements yet is still able to evade important host antiviral innate immune responses. Clearer understanding of the host and viral mechanisms affecting HBV replication and persistence is necessary to design more effective therapeutic strategies aimed at improving the management of patients with chronic HBV infection to eventually achieve viral eradication. This article focuses on summarising the current knowledge of factors influencing the course of HBV infection, giving emphasis on the use of novel assays and quantitative serological and intrahepatic biomarkers as tools for predicting treatment response and disease progression.
SourceAvailable from: Jianguo Wu[Show abstract] [Hide abstract]
ABSTRACT: Acute respiratory tract infections (ARTIs) are associated with significant morbidity and mortality worldwide, especially in children under the age of 5 years. Almost 2 million children die from ARTIs each year, and most of them are from developing countries. The prevalence and correlation of pathogens in ARTIs are poorly understood, but are critical for improving case prevention, treatment, and management. In this study, we investigated the prevalence and correlation of infectious agents in children with ARTIs. A total of 39,756 children with one or more symptoms, including fever, cough, sore throat, tonsillitis, pharyngitis, herpangina, pneumonia, and bronchiolitis, were enrolled in the study. All patients were hospitalized in Wuhan Children's Hospital between October 1, 2010 and September 30, 2012, and were evaluated for infectious agents. Pathogens, including Mycoplasma pneumoniae, influenza A virus, influenza B virus, adenoviruses, respiratory syncytial virus, parainfluenza virus, Legionella pneumophila, Chlamydophila pneumoniae, and Coxiella burnetii, were screened simultaneously in patient blood samples using anti-pathogen IgM tests. Regression analysis was used to reveal correlations among the pathogens. Our results showed that one or more pathogens were identified in 10,206 patients, and that Mycoplasma pneumoniae, adenoviruses, and influenza B virus were the leading infectious agents. Mixed-infections of pathogens were detected in 2,391 cases, with Mycoplasma pneumoniae as the most frequent pathogen. The most common agents in the co-infections were Mycoplasma pneumoniae and influenza B virus. Regression analysis revealed a linear correlation between the proportion of mixed infections and the incidence of multi-pathogen infections. The prevalence of infectious agents in children with ARTIs was determined. Equations were established to estimate multiple infections by single-pathogen detection. This revealed a linear correlation for pathogens in children with ARTIs. This study provides useful information for improving case prevention and management.PLoS ONE 03/2015; 10(3):e0119170. DOI:10.1371/journal.pone.0119170 · 3.53 Impact Factor
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ABSTRACT: Toll-like receptor 2 (TLR2) plays an important role in the immunopathogenesis of hepatitis B virus (HBV) infection. The relationship between TLR2 expression and clinical outcome of chronic HBV infection is not yet elucidated in details so far. Here, we employed clinical cohorts to investigate TLR2 expression and function in different phases of HBV infection and dynamic changes of TLR2 expression in HBeAg-positive chronic hepatitis B (CHB) patients during antiviral therapy. TLR2 was mainly expressed in monocytes and its ligand stimulation resulted in TNF-α, IL-6 and IL-10 production. Serum soluble TLR2 (sTLR2) levels were negatively correlated with TLR2 mRNA in PBMC. As compared with immunotolerant carriers and inactive carriers, CHB patients showed an elevated TLR2 expression and TNF-α, IL-6 induction in PBMC, but had a decreased level of sTLR2 in serum. However, TLR2 expression and TNF-α induction in monocytes of CHB patients was remain lower than healthy controls. Furthermore, higher TLR2 expression in PBMCs and lower level of sTLR2 in serum at baseline was predictive of a complete response to 52weeks of telbivudine (LdT) therapy. Temporal dynamic analysis showed that TLR2 expression was restored with viral suppression and ALT normalization from week 12 to 24. However, peg-IFN-α-2a therapy induced a slightly decline in TLR2 expression. In conclusion, TLR2 expression and function in monocytes were impaired by chronic HBV infection. Higher TLR2 levels in PBMC and lower sTLR2 in serum at baseline were associated with a complete response to LdT therapy, and dynamic TLR2 expression was differently regulated by LdT and peg-IFN-α-2a therapy. Copyright © 2015. Published by Elsevier B.V.Antiviral Research 03/2015; 118. DOI:10.1016/j.antiviral.2015.03.004 · 3.43 Impact Factor
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ABSTRACT: Hepatitis B virus (HBV) infection is a major cause of liver diseases. However, the mechanisms underlying HBV infection and pathogenesis remain largely unknown. The sex-determining region Y box 4 (Sox4) is a transcriptional factor, which preferentially regulates the development of various organs, tissues, and cancers. But, the role of Sox4 in viral infection and pathogenesis has not been elucidated. Here, we demonstrated that Sox4 is up-regulated by HBV, and revealed the mechanism by which HBV regulates Sox4 expression. First, HBV stimulates Sox4 expression through transcriptional factor Yin Yang 1 (YY1), which binds to Sox4 promoter to activate Sox4 transcriptional activity. Second, miR-335, miR-129-2 and miR-203 inhibit Sox4 expression by targeting its mRNA 3'UTR, while HBV suppresses the microRNAs expression, resulting in up-regulating Sox4 post-transcriptionally. Third, Sox4 protein is degraded by proteasome, while HBV surface protein (HBsAg) prevents Sox4 from degradation by directly interacting with the protein, thereby enhancing Sox4 production post-translationlly. More interestingly, HBV-activated Sox4 in turn facilitates HBV replication by direct binding to the viral genome via its HMG box. Thus, this study revealed a novel positive feedback mechanism by which Sox4 production and HBV replication are tightly correlated.Scientific Reports 01/2015; 5:10066. DOI:10.1038/srep10066 · 5.08 Impact Factor