Pathological impact of hepatitis B virus surface proteins on the liver is associated with the host genetic background
Authors: Roberta Montalbano
Daniel Zahner
Tomomitsu Matono
Elke Roeb
Malvika Pompaiah
Wolfram Gerlich
Kurt Reifenberg
Hans-Joachim Mollenkopf
Dirk Schröder
Johannes Stiefel
Dieter Glebe
Tilman Würger
Martin Roderfeld
Yuri Churin
Matthias Ocker
Journal: PLoS ONE (2014)
Discipline: Multidisciplinary
Keywords: HBV; surface proteins; liver; transgenic mice; genetic background
Affiliations: Department of Gastroenterology, Justus Liebig University, Giessen, Germany., Core Facility Microarray, Max Planck Institute for Infection Biology, Berlin, Germany., Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany., Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany., Central Laboratory Animal Facility, Johannes Gutenberg University, Mainz, Germany., Division of Animal Welfare and Ethology, Justus Liebig University, Giessen, Germany., Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, Justus Liebig University, Giessen, Germany.

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. 

Retracted: No

PubPeer comments:
 May 2015 correction, which reads:  *In Fig 4A of the original published article, some of the bands from the c-Jun at 26 weeks panel, were run on a single gel, but were not adjacent in the original gel and were spliced together to improve ease of readability. In the revised image the authors have provided the unspliced panel indicating that for this panel Lane 9 is male C57BL 6 and Lane 10 is female HBVTg 6 unlike in the other panels where Lane 9 is female HBVTg 6 and Lane 10 is male C57BL 6. In addition, the authors reproduced the beta-actin control for both Week 26 and 52. In the revised figure, the authors have provided the correct beta-actin control for Week 52. The original raw files for the gel images are provided as supplementary files in addition to the revised figure. The authors apologize for the errors and any inconvenience that it may have caused. * Here is a duplication in Figure 4, marked with red and blue boxes, as reported in May 2014. The duplication was corrected as well, but not really mentioned in the text of the correction. ![file] The cuts in Figure 4A were also part of the May 2014 report, shown here with green arrows. ![file] I thank the authors for correcting these concerns. ,