Hepatitis-B-Virusinfektion

Forschungsschwerpunkte

• Rolle der innaten Immunantworten in der Kontrolle der Hepatitis-B-Virusinfektion
• Regulation der HBV-Replikation durch miRNAs und Wirtsfaktoren
• Immuntherapeutische Ansätze zur Behandlung chronischer HBV-Infektion
• Tiermodelle für HBV-Forschung
   

Projekt

Weltweit sind ca. 350 Millionen Menschen mit dem chronischen Hepatitis-B-Virus (HBV) infiziert. Die verfügbaren Therapien mit Interferonen und Nukleosidanaloga stoßen jedoch an ihre Grenzen. Ein langfristiges Projekt unserer Gruppe ist die Entwicklung von geeigneten therapeutischen Vakzinen für die Behandlung chronischer HBV-Infektionen. In jüngerer Zeit hat die Rolle der angeborenen Immunantwort für die Kontrolle der HBV-Infektion an Wichtigkeit gewonnen. Unser Interesse ist die gezielte Aktivierung der angeborenen und antiviralen Immunantwort in der Leber. Ein wichtiger Aspekt ist der gegenseitige Einfluss von angeborener und adaptiver Immunantwort in der HBV-Infektion. Darüber hinaus untersuchen wir auch die epigenetische Kontrolle der Zelldifferenzierung sowie Metabolismen und ihre Beziehungen zu HBV-Infektionen.

Arbeitsgruppe

Leiter

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​Thekla Kemper, MTA
Tel.: +49 (0)201 723 3585

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​Xueyu Wang, M. Med.
Tel.: +49 (0)201 723 3540
E-Mail: xueyu.wang@uni-due.de

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​Qian Li, M. Med.
Tel.: +49 (0)201 723 3540
E-Mail: qian.li@uni-due.de

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​Shi Liu, M. Med.
Tel.: +49 (0)201 723 3540
E-Mail: shi.liu@uni-due.de

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​Yong Lin, M. Med.
Tel.: +49 (0)201 723 3540
E-Mail: yong.lin@uni-due.de

Ausgewählte Publikationen

Zhang, J-M, Xu Y, Wang X-Y, Yin Y-K, Wu X-H, Weng, X-H, and Lu, M. (2007) Coexistence of hepatitis B surface antigen (HBsAg) and heterologous subtype-specific antibodies to HBsAg among patients with chronic hepatitis B virus infection. Clin Infect Dis. 44(9):1161-9.

Lu, M, Menne S, Yang D L, Xu Y, and Roggendorf M. (2007) Immunomodulation as an option for treatment of chronic hepatitis B virus infection: preclinical studies in the woodchuck model. (Review). Expert Opinion of Investigational Drugs: 16: 787-801.

Roggendorf M, Schulte I, Xu Y, and Lu M. (2007) Therapeutic vaccination in chronic hepatitis B: Pre-clinical studies in the woodchuck model. J. Viral. Hepat. 14 (Suppl. 1) 51-57.

Wu J, Lu M, Meng Z, Trippler M, Broering R, Szczeponek A, Krux F, Dittmer U, Roggendorf M, Gerken G, and Schlaak J. (2007) Toll-like receptor-mediated control of HBV replication by non-parenchymal liver cells in mice. Hepatology 46: 1769-1778.

Lu M, Yao X, Xu Y, Lorenz H, Dahmen U, Chi H, Dirsch O, Kemper T, He L, Glebe D, Gerlich W, Wen Y M, and Roggendorf M. (2008) Combination of an antiviral drug and immunomodulation against hepadnaviral infection in the woodchuck model. J. Virol, 82(5):2598-603.

Meng Z, Qiu S, Zhang X, Wu J, Schreiter T, Xu Y, Yang D, Roggendorf M, Schlaak J, and Lu M. (2009) Inhibition of Woodchuck Hepatitis Virus Gene Expression in primary hepatocytes by siRNA enhances the cellular antiviral gene expression. Virology, 384 :88–96.

Wu, J. Meng, Z., Jiang, M., Pei, R. J., Trippler, M., Broering, R., Bucchi, A., Sowa, J., Dittmer, U., Yang, D., Roggendorf, M., Gerken, G., Lu, M., and Schlaak, J. (2009) Hepatitis B virus Suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and non-parenchymal liver cells. Hepatology, 49: 1132-40.

Zhang, X. Y., Meng, Z. J., Qiu, S., Xu, Y., Yang, D., Schlaak, J., Roggendorf, M., and Lu, M. (2009) Lipopolysaccharide-induced innate immune response in primary hepatocytes downregulates woodchuck hepatitis virus replication via inerferon-independent pathways. Cell. Microbiol. 11:1624-1637.

Roggendorf, M., Yang, D., and Lu, M. (2010) The woodchuck: a model for therapeutic vaccination against hepadnaviral infection. Pathologie Biologie 58(4):308-14. (invited review)

Wang, B., Tian, Y., Meng, Z., Min, J., Wei, B-.-Q., Tao, Y.-Q., Fan, W., Li, A., Bao, J., Li, X., Zhang, Z., Wang, Z.-D., Wang, H., Roggendorf, M., Lu, M., and Yang, D.-L. (2011) Establishing a new animal model for hepadnaviral infection: Susceptibility of Chinese Marmota-species to woodchuck hepatitis virus infection. J Gen Virol, 92:681-91. (corresponding author)

Zhang, X., Zhang, E., Ma, Z., Pei, R., Jiang, M., Schlaak, J. F., Roggendorf, M., and Lu M. (2011) Modulation of HBV Replication and Hepatocyte Differentiation by MicroRNA-1. Hepatology: 53(5):1476-85.

Zhang, Z. H., Li, L., Zhao, X. P., Glebe, D., Leistner, C., Zhang, Z. M., Wang, B. J., Yang, Y., Gerlich, W., Roggendorf, M., Li, X., Lu, M., and Yang, D. L. (2011) Elimination of hepatitis B virus surface antigen and appearance of neutralizing antibodies in chronically infected patients without virus clearance. J. Viral. Hepat.: 18, 424–433. (corresponding author)

Yin, Y., Wu, C.-C., Song, J., Wang, J.-Z, Zhang, E., Liu, H., Yang, D.-L., Chen, X.-W., Lu, M., and Xu, Y. (2011) DNA immunization with fusion of CTLA-4 to hepatitis B virus core protein enhanced Th2 type responses and cleared HBV with an accelerated kinetic. PLoS ONE 6: e22524.

Zhang, E., Zhang, X., Liu, J., Wang, B., Tian, Y., Ma, Z., Xu, Y., Dittmer. U., Roggendorf, M., Yang, D., and Lu, M. (2011) The expression of PD-1 ligands and their involvement in regulation of T cell functions in acute and chronic woodchuck hepatitis virus infection. PLoS One 6(10): e26196.

Wu, C.-C., Deng, W, Deng, L., Cao, L., Qin, B, Li S,Wang Y, Pei R, Yang, D., Lu, M., Chen, X. (2012) Amino acid substitutions at positions 122 and 145of hepatitis B virus surface antigen(HBsAg) determine the antigenicity and immunogenicity of HBsAg and influence in vivo HBsAg clearance. J. Virol. 86: 4658–69.(corresponding author)

Zhang X., Kraft, A., Boering R., Schlaak J. F., Dittmer, U., Lu M. (2012) Preclinical development of TLR ligands as drugs for the treatment of chronic viral infection. Expert Opinion Drug Discovery 7(7): 597-61. (invited review)

Zhang, X., Ma, Z., Liu, H., Meng, Z., Boering, R., Yang, D., Schlaak, F. S., Roggendorf, M., Lu, M. (2012) Role of Toll-like receptor 2 in the immune response against hepadnaviral infection. J Hepatol. 57: 522-8.

Kosinska A., Johrden, L., Zhang, E., Fiedler, M., Mayer, A., Wilder, O., Lu, M., Roggendorf, M. (2012) DNA Prime-Adenovirus Boost Immunization Induces Vigorous, Multifunctional T-cell response against Hepadnaviral Proteins in Mouse and Woodchuck mode. J Virol., 86(17): 9297-310.

Chen, J., Wu, M., Zhang, X., Zhang, W., Zhang, Z., Chen, L., He, J., Zheng, Y., Chen, C., Wang, F., Hu, Y., Zhou, X., Wang, C., Xu, Y., Lu, M., Yuan, Z. H. (2013) Hepatitis B virus polymerase impairs interferon-α-induced STATs activation through inhibition of importin-α5 and protein kinase C-δ. Hepatology, 57: 470-82.

Meng, Z., Zhang, X., Wu, J., Pei, R., Xu, Y., Yang, D., Roggendorf, M., Lu, M. (2013) RNAi induces innate immunity through multiple cellular signalling pathways. PLoS One 8: e64708.

Kosinska, A. D., Zhang, E., Johrden, L., Liu, J., Seiz, P. L., Zhang, X., Ma, Z., Kemper, T., Fiedler, M., Glebe, D., Wildner, O., Dittmer, U., Lu, M., and Roggendorf, M. (2013) Combination of the DNA prime-adenovirus boost immunization with entecavir elicits sustained control of chronic hepatitis B in the woodchuck model. PLoS Pathogens, 9(6): e1003391.

Zhang, X. Hou, J., and Lu, M. (2013). Regulation of Hepatitis B virus Replication by Epigenetic Mechanisms and MicroRNAs. Frontiers in Genetics. 4:202v online. (review)

Liu, J., Jiang, M., Ma, Z., Dietze, K. K., Zelinsky, G., Yang, D., Dittmer, U., Schlaak, J. F., Roggeodorf, M., Lu, M. (2013) TLR1/2 Ligand-Stimulated Mouse Liver Endothelial Cells secrete IL-12 and Trigger CD8+ T-Cell Immunity in vitro. J. Immunol. 191(12):6178-90.

Liu, J., Zhang, E., Ma, Z., Wu, W., Kosinska, A., Zhang, X., Möller, I., Seiz, P., Glebe, D., Wang, B., Yang, D., Lu, M., Roggendorf, M. (2014) Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadanviral infection. PLoS Pathogens, 10(1): e1003856.

Wang, J., Wang, B., Huang, S., Song, Z., Wu, J., Zhang, E., Zhu, Z., Zhu, B., Yin, Y., Lin, Y., Xu Y, Zheng. X., Lu, M., Yang, D. (2014) Immunosuppressive drugs modulate the replication of hepatitis B virus (HBV) in a hydrodynamic injection mouse model. PLoS One, 9(1): e85832.

Yang, J., Zhang, E., Liu, F., Zhang, Y., Zhong, M., Li, Y., Zhou, D., Chen, Y., Cao, Y., Xiao, Y., He, B., Yang, Y., Sun, Y., Lu, M., Yan, H. (2014) Flagellins of Salmonella Typhi and non-pathogenic Escherichia coli are differentially recognized through NLRC4 pathway in macrophage. J Innate Immunity, 6:47–57. (corresponding author)

Pei, R., Qin., B., Zhang, X., Zhu W, Kemper, T., Ma, Z., Trippler, M, Schlaak, J., Chen, X., and Lu M. (2014) Interferon-induced protein with tetratricopeptide repeats 1 and 2 are cellular factors that limit hepatitis B virus replication. J. Innate Immunity, 6:182-191.

Xu, L., Beckebaum, S., Iacob, S., Wu, G., Kaiser, G., Radtke, A., Liu, C., Kabar, I., Schmidt, H. H., Zhang, X., Lu, M., Cicinnati V. R. (2014) MicroRNA-101 inhibits human hepatocellular carcinoma progression through enhancer of zeste homologue 2 downregulation and increased cytostatic drug activity. J Hepatol, ;60(3):590-8.

Meng, Z., Ma, Z., Zhang, E., Kosinska, A., Liu, J., Zhang, X., Zhou T., Wu, J., Dahmen, U., Dirsch, O., Yang, D., Roggendorf, M., and Lu, M. (2014) Novel woodchuck hepatitis virus (WHV) transgene mouse models show sex-dependent WHV replicative activity and development of spontaneous immune responses to WHV proteins. J. Virol. 88 (3):1573-81.

Jiang, M., Broering, R., Trippler, M., Poggenpohl, L., Fiedler, M., Gerken, G., Lu, M., and Schlaak, J. F. (2014) Toll-like receptor-mediated immune responses are attenuated in the presence of the hepatitis B virus surface antigen. J Viral Hepatitis online.

Song, J., Zhou, Y., Li, S., Wang, B., Zheng, X., Wu, J., Gibbert, K., Dittmer, U., Lu, M., and Yang, D. (2014) Susceptibility of different hepatitis B virus isolates to interferon-alpha in a mouse model based on hydrodynamic injection. PLoS One, 9(3): e90977.

Wang, B., Zhu, Z., Zhu, B., Wang, J., Song, Z., Huang, S., Fan, W., Tao, Y., Wang, Z., Wang, H., Lu., M., Yang, D. (2014) Nucleoside Analogues Alone or Combined with Vaccination Prevent Hepadnavirus Viremia and Induce Protective Immunity: Alternative Strategy for Hepatitis B Virus Post-exposure Prophylaxis. Antiviral Res. 105:118-25.

Cao, L., Wu, C., Shi, H., Gong, Z., Zhang, E., Wang, H., Zhao, K., Liu, S., Li, S., Gao, X., Wang Y, Lu, M., Chen, X. Coexistence of hepatitis B virus quasispecies changes the replication activity and the ability to induce host antibody and celluar immune responses. J Virol. online.