Pathological impact of hepatitis B virus surface proteins on the liver is associated with the host genetic background.

Abstract

BACKGROUND:

While 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.

METHODS:

The 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.

RESULTS:

Expression 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.

CONCLUSIONS:

Extent of liver injury, fibrosis, and tumour development induced by hepatic HBV surface protein expression considerably depends on host genetic background.

• Authors: Yuri Churin, Martin Roderfeld, Johannes Stiefel, Tilman Würger, Dirk Schröder, Tomomitsu Matono, Hans-Joachim Mollenkopf, Roberta Montalbano, Malvika Pompaiah, Kurt Reifenberg, Daniel Zahner, Matthias Ocker, Wolfram Gerlich, Dieter Glebe, Elke Roeb
• Journal: PloS one (PLoS One) Vol. 9 Issue 3 Pg. e90608 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24594856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Viral Structural Proteins
• PERK kinase
• eIF-2 Kinase

Topics

• Animals
• Female
• Gene Expression Regulation
• Hepatitis B (complications, genetics, metabolism, pathology)
• Hepatitis B virus (physiology)
• Host-Pathogen Interactions
• Liver (metabolism, pathology, virology)
• Liver Cirrhosis (etiology, genetics)
• Liver Neoplasms (etiology, genetics)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Phosphorylation
• Signal Transduction
• Viral Structural Proteins (genetics)
• eIF-2 Kinase (metabolism)