EN
Project - B05:
The role of infected hepatocytes in regulating intrahepatic immunity
Project leader:
Prof. Dr. rer. nat. Maura Dandri
Summary
The tolerogenic microenvironment that characterises the liver makes this organ particularly attractive for pathogens, like human hepatitis viruses, which often establish chronic infection by specifically infecting the hepatocytes. To meet their replication requirements, hepatitis viruses promote alterations of the antiviral innate defenses and metabolic derangements. The major aetiological agent of chronic viral hepatitis worldwide is hepatitis B virus (HBV), a strictly hepatotropic DNA virus. The pathological consequences of chronic HBV (CHB) infection are further aggravated by co- or super-infection with the hepatitis Delta virus (HDV), a defective RNA virus that relies on HBV envelope proteins to infect the human hepatocytes. The molecular mechanisms triggering such a severe form of viral hepatitis are unknown and antiviral treatments are urgently needed to hinder the progressive course of chronic hepatitis D (CHD). Moreover, it remains unclear to which extent virus-mediated alterations of the hepatocytes influence hepatic immune regulation and pathogenesis. We hypothesise that infected hepatocytes play a key role in regulating intrahepatic cell-to-cell communication and the recruitment of immune cells, thereby determining the pathogenesis of viral hepatitis. Elucidating virus-mediated hepatocyte reprogramming and the broad repertoire of signalling molecules and chemokines (hepatokines) released from infected cells represent a key effort in the development of curative therapies.
Project plan
Our central hypothesis is that hepatocytes play a key role in influencing immune regulation in the liver. Based on this hypothesis, we aim to elucidate virus-mediated changes occurring in human hepatocytes, as well as the impact of such alterations on uninfected bystander cells, immune cell recruitment and functionality in the liver. To achieve our aims, we will employ in vitro and in vivo infection models based on humanised mice as well as liver biopsies from chronically infected people (CHD, CHB).
Our work programme has the following work packages (WP):
WP1: To characterise functional alterations occurring in human hepatocytes upon HBV/HDV infection.
WP2: To investigate potential dysfunctions occurring in immune cells recruited to the liver by infected hepatocytes.
WP3: To determine the impact of antiviral therapies on virus-induced hepatocyte dysfunction.
Project related publications
Allweiss L, Giersch K, Pirosu A, Volz T, Muench RC, Beran RK, Urban S, Javanbakht H, Fletcher SP, Lütgehetmann M, Dandri M. Therapeutic shutdown of HBV transcripts promotes reappearance of the SMC5/6 complex and silencing of the viral genome in vivo. Gut 2022;372-381. Open access.
Dandri M, Volmari A, Lütgehetmann M. The hepatitis delta virus and chronic hepatitis D. J Hepatol 2022;77:1448-1450. doi: 10.1016/j.jhep.2022.05.022. Open access.
Giersch K, Bhadra OD, Volz T, Allweiss L, Riecken K, Fehse B, Lohse AW, Petersen J, Sureau C, Urban S, Dandri M#, Lütgehetmann M#. Hepatitis delta virus persists during liver regeneration and is amplified through cell division both in vitro and in vivo. Gut 2019;68:150-157. Open access.
Wedemeyer H, Schöneweis K, Bogomolov P, Blank A, Voronkova N, Stepanova T, Sagalova O, Chulanov V, Osipenko M, Morozov V, Geyvandova N, Sleptsova S, Bakulin IG, Khaertynova I, Rusanova M, Pathil A, Merle U, Bremer B, Allweiss L, Lempp FA, Port K, Haag M, Schwab M, Zur Wiesch JS, Cornberg M, Haefeli WE, Dandri M, Alexandrov A, Urban S. Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial. Lancet Infect Dis 2023;23:117-129. doi: 10.1016/S1473-3099(22)00318-8.
Allweiss L, Volmari A, Suri V, Wallin JJ, Flaherty JF, Manuilov D, Downie B, Lütgehetmann M, Bockmann JH, Urban S, Wedemeyer H, Dandri M. Blocking viral entry with bulevirtide reduces the number of HDV-infected hepatocytes in human liver biopsies. J Hepatol 2024:S0168-8278(24)00114-4. doi: 10.1016/j.jhep.2024.01.035. Open access.
Giersch K, Hermanussen L, Volz T, Kah J, Allweiss L, Casey J, Sureau C, Dandri M#, Lütgehetmann M#. Murine hepatocytes do not support persistence of Hepatitis D virus mono-infection in vivo. Liver Int 2021;41:410-419. doi: 10.1111/liv.14677. Open access.
Kah J, Koh S, Volz T, Ceccarello E, Allweiss L, Lütgehetmann M, Bertoletti A, Dandri M. Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection. J Clin Invest 2017;127:3177-88. doi: 10.1172/JCI93024. Epub 2017 Jul 24.
Tham CYL, Kah J, Tan AT, Volz T, Chia A, Giersch K, Ladiges Y, Loglio A, Borghi M, Sureau C, Lampertico P, Lütgehetmann M, Dandri M#, Bertoletti A#. Hepatitis Delta Virus Acts as an Immunogenic Adjuvant in Hepatitis B Virus-Infected Hepatocytes. Cell Rep Med 2020 Jul 21;1(4):100060. doi: 10.1016/j.xcrm.2020.100060.
Oehler N, Volz T, Bhadra OD, Kah J, Allweiss L, Giersch K, Bierwolf J, Riecken K, Pollok JM, Lohse AW, Fehse B, Petersen J, Urban S, Lütgehetmann M, Heeren J, Dandri M. Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism. Hepatology 2014;60:1483-93. doi: 10.1002/hep.27159.
Giersch K, Allweiss L, Volz T, Helbig M, Bierwolf J, Lohse AW, Pollok JM, Petersen J, Dandri M#, Lütgehetmann M#. Hepatitis Delta co-infection in humanised mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection. J Hepatol 2015;63:346-53. doi: 10.1016/j.jhep.2015.03.011. Open access.
# equally contributing authors