Project Details
TRR 179: Determinants and dynamics of elimination versus persistence of hepatitis virus infection
Subject Area
Medicine
Term
since 2016
Website
Homepage
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 272983813
Infections with hepatitis viruses are a major public health concern causing high morbidity and mortality worldwide. The underlying reasons are manifold like e.g. the high propensity to establish persistence, the high global prevalence of viral hepatitis and a high proportion of undiagnosed infections. The last few years have seen major developments in the field of viral hepatitis including cure of chronic Hepatitis C and a new therapy for hepatitis D virus (HDV) infection with the entry inhibitor Myrcludex B (Bulevirtide). Moreover, important aspects of the biology of enteric hepatitis viruses, i.e. hepatitis A virus (HAV) and hepatitis E virus (HEV), have been discovered. The outcome of hepatitis virus infections, either acute self-limiting or persistent, is a dynamic process that is governed by the complex interplay of host and viral factors. Deciphering the mechanisms and dynamics orchestrating this complex interplay is the central aim of TRR179. Required approaches must e.g. take into account the tolerogenic liver microenvironment, the cross-talk between innate and adaptive immune responses, the duration of immune stimulation and the amount of viral antigen. Therefore, an integrative and highly interdisciplinary approach is required.During the first funding period (FP), we made important progress. Capitalizing on that and including novel scientific discoveries/ technologies, during the second FP we will retain our main focus on the fundamental principles underlying hepatitis virus elimination versus persistence, but add important new aspects. These include novel therapeutic concepts towards cure of HBV and HDV infections. We will strengthen comparative research on acute, self-limiting hepatitis viruses by the inclusion of HEV and integrate virus-host co-evolution to understand the adaptation mechanisms underlying hepatitis virus persistence. Another important aspect will be the integration of novel technologies including single-cell transcriptomics and epigenomics, mass cytometry for high-parametric analyses of immune cells and more authentic cell culture models. In addition, we will integrate structure biology to resolve some fundamental aspects of HBV biology. This initiative thus provides the framework to address the salient questions in the field and to conduct studies at the molecular and cellular level, translate obtained results into relevant preclinical in vivo systems and validate the findings in hepatitis virus-infected individuals. Although TRR179 focuses on hepatitis viruses, the basic principles and mechanisms uncovered here will likely be applicable to persistent infections by other pathogens. In this respect, TRR179 has high innovation potential reaching far beyond viral hepatitis.
DFG Programme
CRC/Transregios
Current projects
- 01 - Fate and function of memory-like virus-specific CD8+ T cells in chronic viral hepatitis (Project Heads Hofmann, Maike ; Thimme, Robert )
- 02 - Virus-specific CD8+ T cell responses in hepatitis B virus/ hepatitis D virus co-infection: mechanisms of failure and strategies for restoration (Project Head Neumann-Haefelin, Christoph )
- 04 - Regulation of virus-specific CD4 T helper cell responses in viral hepatitis (Project Head Böttler, Tobias )
- 05 - The impact of hepatic myeloid cells on antiviral CD8 T cell immunity in the liver (Project Head Knolle, Percy Alexander )
- 06 - Role of platelets in control and clearance of hepatitis B virus infection via modulation of liver tissue environment and metabolism (Project Head Heikenwälder, Mathias )
- 07 - Dissecting NK cell reactivity against hepatitis B/D virus and in hepatitis C virus infection (Project Head Cerwenka, Adelheid )
- 09 - Control of hepatitis C virus infection by the interferon system and virus – host co-evolution (Project Head Bartenschlager, Ralf Friedrich Wilhelm )
- 10 - Identification of systems properties determining the dynamics of the hepatitis B virus infection cycle and cross-talk to host cell responses (Project Heads Klingmüller, Ursula ; Timmer, Jens )
- 11 - Effects of persistent antiviral signalling on tissue homeostasis and antiviral immunity (Project Heads Binder, Marco ; Pichlmair, Andreas )
- 13 - Dynamics of antiviral immunity against hepatitis B virus in the liver (Project Heads Ntziachristos, Vasilis ; Wohlleber, Dirk )
- 14 - Means of modification and degradation of hepatitis B virus cccDNA (Project Head Protzer, Ulrike )
- 15 - Viral determinants and innate immunity in persistent hepatitis B virus and hepatitis D virus infections (Project Head Urban, Stephan )
- 16 - Role of DNA repair, SUMOylation and nuclear bodies in the formation of the hepatitis B virus cccDNA persistence reservoir (Project Heads Nassal, Michael ; Schreiner, Sabrina )
- 17 - Contribution of innate immune responses to persistence versus clearance of hepatitis C virus and hepatitis A virus infections (Project Head Lohmann, Volker )
- 18 - Combinatorial knock-down/knock-out strategies to reconstitute anti-viral immunity and eliminate persisting hepatitis B virus cccDNA (Project Heads Grimm, Dirk ; Protzer, Ulrike )
- 20 - Impact of interferon-stimulated genes on virus-specific CD8+ T cells and NK cells in viral hepatitis (Project Head Hofmann, Maike )
- 21 - Metabolic regulation of the virus-specific T cell response in viral hepatitis (Project Head Bengsch, Ph.D., Bertram )
- 22 - Impact of the enteric stage of hepatitis A virus and hepatitis E virus on the outcome of liver infection (Project Heads Boulant, Steeve ; Dao Thi, Ph.D., Viet Loan )
- 23 - Dynamics of hepatitis B virus morphogenesis and its alterations during chronic infection (Project Heads Schütz, Anne ; Seitz, Ph.D., Stefan )
- MGK19 - Integrated Research Training Group “Immunovirology” (Project Heads Bauer, Tanja ; Hengel, Hartmut ; Lohmann, Volker ; Ruggieri, Ph.D., Alessia ; Schreiner, Sabrina )
- Z01 - Central tasks of the transregional collaborative research centre 179 (Project Head Bartenschlager, Ralf Friedrich Wilhelm )
- Z02 - High-resolution multi-parametric cell and tissue analysis (Project Heads Andrä, Immanuel Anton ; Bauer, Tanja ; Bengsch, Ph.D., Bertram ; Eils, Roland ; Mogler, Carolin ; Neumann-Haefelin, Christoph ; Schiemann, Matthias )
- Z03 - Experimental and computational single-cell sequencing (Project Heads Herrmann, Carl ; Rippe, Karsten )
Completed projects
- 03 - Generation of effective antiviral CD4 T cell immunity in viral hepatitis and its association to unique signatures of transcription factors (Project Head Raziorrouh, Bijan )
- 08 - Mechanisms of interferon induction by hepatitis D virus and impact of chronic innate immune activation on antiviral immunity (Project Heads Bohne, Felix Mark ; Hornung, Veit ; Knolle, Percy Alexander )
- 12 - Role of the host stress response in the establishment of viral persistence: comparative analysis of hepatitis C virus and hepatitis A virus infection (Project Head Ruggieri, Ph.D., Alessia )
Applicant Institution
Ruprecht-Karls-Universität Heidelberg
Co-Applicant Institution
Albert-Ludwigs-Universität Freiburg; Technische Universität München (TUM)
Participating Institution
Deutsches Krebsforschungszentrum (DKFZ)
Spokesperson
Professor Dr. Ralf Friedrich Wilhelm Bartenschlager