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Interferon Regulated Immune Responses in Viral Hepatitis

English title Interferon Regulated Immune Responses in Viral Hepatitis
Applicant Heim Markus
Number 166202
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.04.2016 - 31.03.2019
Approved amount 916'623.00
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Keywords (4)

Liver; Interferon; Viral hepatitis; Hepatology

Lay Summary (German)

Lead
Weltweit leiden über 500 Millionen Menschen an Leberentzündungen, die von Hepatitis Viren verursacht werden. Hepatitis B und Hepatitis C Viren können chronische Entzündungen verursachen, die über Jahrzehnte zu einer Leberzirrhose führen können. Die Immunantwort auf diese Viren wird wesentlich vom sogenannten angeborenen Immunsystem beeinflusst. Dabei spielen Interferone eine zentrale Rolle.
Lay summary

Inhalt und Ziel des Forschungsprojektes:

Im Rahmen dieses Forschungsprojekts wird die Rolle von Interferon Lambda 4 (IFNl4) für die Immunabwehr von Hepatitis Viren untersucht. IFNl4 ist deshalb von besonderem Interesse, weil seine Expression von einem genetischen Polymorphismus bestimmt wird. Das bedeutet, dass nicht alle Menschen IFNl4 herstellen können, weil in ihrem Erbgut ein defektes Gen für IFNl4 vorhanden ist. Vor einigen Jahren wurde in grossen genetischen Studien überraschenderweise entdeckt, dass genau dieses IFNl4 den Ausgang einer Infektion mit Hepatitis C Viren massgebend bestimmt. Das ist erstaunlich, weil es noch viele weitere Interferone gibt, die ebenfalls gegen das Hepatitis C Virus wirksam sind. Das beste Bespiel ist Interferon alpha 2, welches rekombinant hergestellt und während den letzten 2 Jahrzehnten für die Behandlung der chronischen Hepatitis C eingesetzt wurde. Wieso genau das IFNl4 so wichtig ist für den natürlichen Verlauf einer Hepatitis C Infektion ist nicht bekannt. Unser Forschungsprojekt wird dieser Frage nachgehen.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts:

Wir erhoffen uns von dem Projekt grundlegende neue Erkenntnisse über das angeborene Immunsystem in der Leber. Diese Erkenntnisse könnten mittelfristig zur Entwicklung einer Impfung gegen Hepatitis C beitragen. Eine solche Impfung ist notwendig um die weltweite Hepatitis C Epidemie zu kontrollieren. 

Direct link to Lay Summary Last update: 25.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Interferon lambda 4 can directly activate human CD19 + B cells and CD8 + T cells
Coto-Llerena Mairene, Lepore Marco, Spagnuolo Julian, Di Blasi Daniela, Calabrese Diego, Suslov Aleksei, Bantug Glenn, Duong Francois HT, Terracciano Luigi M, De Libero Gennaro, Heim Markus H (2020), Interferon lambda 4 can directly activate human CD19 + B cells and CD8 + T cells, in Life Science Alliance, 4(1), e201900612-e201900612.
Liver biopsy derived induced pluripotent stem cells provide unlimited supply for the generation of hepatocyte-like cells
Calabrese Diego, Roma Guglielmo, Bergling Sebastian, Carbone Walter, Mele Valentina, Nuciforo Sandro, Fofana Isabel, Campana Benedetta, Szkolnicka Dagmara, Hay David C., Tchorz Jan, Bouwmeester Tewis, Wieland Stefan, Heim Markus H. (2019), Liver biopsy derived induced pluripotent stem cells provide unlimited supply for the generation of hepatocyte-like cells, in PLOS ONE, 14(8), e0221762-e0221762.

Collaboration

Group / person Country
Types of collaboration
Volker Roth, Department of Mathematics and Computer Science, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Christoph Hess, Department of Biomedicine, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Gerald Schwank, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Luigi Terracciano Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Rune Hartmann, Aarhus University, Denmark Denmark (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
185371 Innate Immunity in Viral Hepatitis 01.04.2019 Project funding (Div. I-III)
147089 Innate Immune Response in Hepatitis C Virus Infections 01.04.2013 Project funding (Div. I-III)

Abstract

Interferons (IFNs) are central regulators of the host immune response to viral hepatitis. T-cell derived IFNgamma is a major antiviral effector controlling both hepatitis C virus and hepatitis B virus infection. IFNalpha is being used since 30 years for treatment of chronic hepatitis B (CHB) and C (CHC). More recently, IFNlambda4 has been identified as a key regulator of the immune response to HCV. The IFNlambda4 gene exists in two major allelic variants. The ancestral allele encodes a fully functional IFNlambda4. An insertion mutation (changing a G to a TT) disrupts the open reading frame of IFNlambda4. Genome wide association studies discovered a highly significant association of the TT allele with spontaneous clearance of HCV. It is presently unclear why IFNlambda4 is a liability in case of an HCV infection. We hypothesize that IFN?4 negatively regulates the cellular immune response to HCV. In this application, we propose three subprojects that investigate different aspects of the IFN? system in viral hepatitis, with a focus on the specific role of IFN?4 in the host response to HCV.In subproject 1 we will study the biochemistry, physiology, tissue distribution and natural regulation of IFN?4. In subproject 2 we will study the regulation of the IFN? receptor. Contrary to the ubiquitous expression of the IFNa receptor in all cell types and organs, IFN? receptor expression is restricted mainly to epithelial cells. However, its expression can be induced in other cell types such as hepatocytes or dendritic cells. A better understanding of the regulation of IFN? receptor expression should provide important insights into the biological function of the IFN? system. In subproject 3 we plan to identify the IFN? responsive immune cells and to elucidate the cell-cell network and the cytokines involved that regulate the immune response to HCV.Simultaneously with these subprojects focused on the IFN? system, we plan to develop human biopsy derived liver organoids as an experimental model to study inter-individual differences in cellular responses to HCV and HBV in subproject 4. Current in vitro models for HCV and HBV are based on few hepatoma derived cell lines and primary human hepatocytes. Both systems have major limitations. Human liver biopsy derived organoids might overcome some of these limitations. Because they can be derived from individual patients they have a unique potential to enable the study of inter-individual differences in cellular responses to hepatitis viruses.
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