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TRR 179:  Determinants and dynamics of elimination versus persistence of hepatitis virus infection

Subject Area Medicine
Term since 2016
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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

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Participating Institution Deutsches Krebsforschungszentrum (DKFZ)
 
 

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