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Universitätsklinikum Essen
Forschung & Lehre

Working Group

Priv.-Doz. Dr. rer. nat. Ruth Bröring

Medical Research Centre
Gastro MFZ, 2nd Floor

The research is focused on hepatic immune responses and virus host interactions in chronic viral hepatitis. The team developed an all-in-one liver cell preparation technique from human tissue, allowing analysis of cell type-specific, liver-specific and disease-specific aspects on cellular and molecular levels [1]. The parenchymal (hepatocyte, PHH) and non-parenchymal cells of the liver [Kupffer cells (KC), liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC)] are part of the innate immune system. They express evolutionarily highly conserved inheritable factors called pathogen recognition receptors (PRRs) [2-4]. They recognize molecular patterns of viruses, bacteria, fungi and parasites that are absent in higher organisms. The PRR represent one of the first lines of defense against invading pathogens and mediate a coordinated immune response through the expression of inflammatory cytokines, antiviral factors, and chemotactic agents. The major goal of research is to reveal the hepatic cytokine network to develop immune-based therapies for chronic liver diseases.

Hepatic expression of interferons and interferon-stimulated genes is a characteristic feature of chronic hepatitis C virus (HCV) infection. Our previous work suggests that hepatocytes respond to chronic exposure with a viral stimulus with increased sensitivity and are believed to be responsible for the persistent interferon response [4]. One of these increased expressed factors is the ubiquitin-like modifier ISG15. We were able to show that ISG15 has a proviral function in HCV infection, high expression of ISG15 directly promotes HCV replication. We demonstrated in preclinical models that therapeutic suppression of ISG15 by siRNA causes a decrease in HCV viral load. This direct, antiviral effect is accompanied by an increase in exogenous or endogenous-mediated interferon responses [5]. Direct interaction of HCV and human non-parenchymal liver cells is one of our ongoing projects.

In contrast to HCV infection, the innate immune system seems not to be activated by infection with the hepatitis B virus (HBV). Chronic HBV infection is one of the leading causes of cirrhosis worldwide with an increased risk of developing liver cell carcinoma. The role of the adaptive and innate immune system in the chronification and immunopathogenesis of this infectious disease has become increasingly important in recent years. The innate immune system of the liver is able to initiate and coordinate efficient immune responses [6]. To avoid this, HBV has developed various evasion strategies. The HBV surface antigen (HBsAg) was described here as an important tolerogen, which dominates the evasion mechanisms of the virus [7, 8]. Aim of current research projects is the detailed analysis of the molecular interactions between the hepatitis B virus and its target cells, the hepatocytes [9], and the non-parenchymal immune cells of the liver. In addition, the question how immune induction and immune control effects HBV-associated carcinogenesis will be addressed [10].

1. Werner M, et al.: All-In-One: Advanced preparation of Human Parenchymal and Non-Parenchymal Liver Cells. PLoS One 2015, 10:e0138655.
2. Wu J, et al.: Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology 2010, 129:363-74.
3. Broering R, et al.: Toll-like receptor-stimulated non-parenchymal liver cells can regulate hepatitis C virus replication. J Hepatol 2008, 48:914-22.
4. Broering R, et al.: Long-term stimulation of Toll-like receptor 3 in primary human hepatocytes leads to sensitization for antiviral responses induced by poly I:C treatment. J Viral Hepat 2014, 21:480-90.
5. Broering R, et al.: The interferon stimulated gene 15 functions as a proviral factor for the hepatitis C virus and as a regulator of the IFN response. Gut 2010, 59:1111-9.
6. Wu J, et al.: Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice. Hepatology 2007, 46:1769-78.
7. Jiang M, et al.: Toll-like receptor-mediated immune responses are attenuated in the presence of high levels of hepatitis B virus surface antigen. J Viral Hepat 2014, 21:860-72.
8. Wu J, et al.: Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatology 2009, 49:1132-40.
9. Zhang Z, et al.: Hepatitis B virus particles activate toll-like receptor 2 signaling initial upon infection of primary human hepatocytes. Hepatology accepted 17-Dec-2019.
10. Zhang R, et al.: Hepatic expression of oncogenes Bmi1 and Dkk1 is up-regulated in hepatitis B virus surface antigen-transgenic mice and can be induced by treatment with HBV particles or lipopolysaccharides in vitro. International journal of cancer 2017, 141:354-63.

Staff members

AG Bröring

Yaojie Liang

M.Sc. Molecular Science, AG Bröring

AG Bröring

Xufeng Luo

M.Sc. Physiology, AG Bröring

AG Bröring

Stefan Schefczyk

M.Sc. Biologie, AG Bröring

Priv.-Doz. Dr. rer. nat. Ruth Bröring
Team Leader

Priv.-Doz. Dr. rer. nat. Ruth Bröring

Diplom Biologin, Arbeitsgruppenleiterin

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