Pathological Impact of Hepatitis B Virus Surface Proteins on the Liver Is Associated with the Host Genetic Background

Abstract

BackgroundWhile the immune pathogenesis caused by hepatitis B virus (HBV) infection has been studied extensively, little is known about direct pathogenic effects of HBV surface proteins. Here, we have investigated pathological cellular effects of HBV surface protein expression in the liver of transgenic mice with different genetic background.MethodsThe impact of HBV surface protein expression on the liver was studied in two mouse strains, BALB/c and C57BL/6. Histology and hydroxyproline assays were performed to investigate liver morphology and fibrosis. Gene expression and signaling were analyzed by microarray, qPCR and Western blotting.ResultsExpression of HBV surface proteins in the liver of transgenic mice induced activation of protein kinase-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2α (eIF2α) phosphorylation. Phosphorylation of eIF2α resulted in activation of the ER stress markers glucose regulated protein (GRP) 78 and pro-apoptotic C/EBP homologous protein (CHOP) in transgenic mice on BALB/c genetic background leading to stronger liver injury and fibrosis in comparison with transgenic mice on C57BL/6 background. Hepatic stellate cells represented the main collagen-producing liver cells in HBV transgenic mice. The key regulators of hepatocyte proliferation, transcription factors c-Jun and STAT3 were activated in HBV transgenic mice. Tumour incidence in transgenic mice was strain- and sex-dependent.ConclusionsExtent of liver injury, fibrosis, and tumour development induced by hepatic HBV surface protein expression considerably depends on host genetic background.

WITHDRAWN: Interleukin-21 receptor gene polymorphism is associated with hepatitis B virus-related hepatocellular carcinoma in Chinese patients

“…However, in the HBVinfected patients, as well as the CHB and HCC patient sub-groups, IL-21R rs2285452 SNP showed deviation from HWE (p=1.60e -6 , 0.002 and 1.94e -8 , respectively). Our findings support previous reports that suggest such deviations from HWE in the case group as a result of genetic drift influenced by the disease [17,18].…”

“…Host genetic factors influence the extent of HBVrelated liver injury, fibrosis, and tumorigenesis [18]. Therefore, designing effective therapeutic strategies against chronic HBV infection requires a better understanding of the host and viral mechanisms that affect HBV replication and persistence [19].…”

Interleukin‐21 receptor gene polymorphism is associated with hepatitis B virus‐related hepatocellular carcinoma in Chinese patients

“…Host genetic factors influence the extent of HBV‐related liver injury, fibrosis, and tumorigenesis . Therefore, designing effective therapeutic strategies against chronic HBV infection requires a better understanding of the host and viral mechanisms that affect HBV replication and persistence.…”

Hepatitis B virus surface protein-induced hPIAS1 transcription requires TAL1, E47, MYOG, NFI, and MAPK signal pathways

“…HBs was initially used only as an immunological marker of HBV infection; however, specific functions of HBs have recently been illuminated, including roles in regulating gene transcription, intracellular signal transduction, genotoxic stress response, apoptotic cell death, and carcinogenesis (Christen et al, 2007;Xu et al, 2009;Pollicino et al, 2011;Ringelhan et al, 2013;Rao et al, 2013;Churin et al, 2014). HBs can be found in the cytoplasm of infected hepatocytes, accumulating in the endoplasmic reticulum (ER), and can trigger apoptosis in the presence of prolonged and severe stress due to induction of oxidative stress (Ringelhan et al, 2013).…”

“…HBs can be found in the cytoplasm of infected hepatocytes, accumulating in the endoplasmic reticulum (ER), and can trigger apoptosis in the presence of prolonged and severe stress due to induction of oxidative stress (Ringelhan et al, 2013). Moreover, HBs induced fibrosis and tumor development by activation of transcription factors c-Jun and STAT3, depending on the host's genetic background (Churin et al, 2014). Moreover, HBs induced fibrosis and tumor development by activation of transcription factors c-Jun and STAT3, depending on the host's genetic background (Churin et al, 2014).…”