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Innate Immune Response in Hepatitis C Virus Infections

English title Innate Immune Response in Hepatitis C Virus Infections
Applicant Heim Markus
Number 147089
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 01.04.2013 - 31.03.2016
Approved amount 819'211.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Medical Microbiology

Keywords (4)

liver; hepatitis c; innate immunity; interferon

Lay Summary (German)

Lead
Die Wechselwirkungen zwischen dem menschlichen Immunsystem und dem Hepatitis C Virus bestimmen den Verlauf der Leberkrankheit und auch das Ansprechen auf die heutigen Therapien. Das Projekt untersucht die Reaktion des menschlichen Körpers auf das Hepatitis C Virus auf molekularer Ebene.
Lay summary

Geschätzte 70'000 Personen sind in der Schweiz mit dem Hepatitis C Virus infiziert. Das Virus vermehrt sich in Leberzellen, und wird von diesen wieder ins Blut abgegeben. Die Übertragung von Mensch zu Mensch geschieht über infiziertes Blut. Die Infektion der Leberzellen führt zu einer chronischen Leberentzündung (Hepatitis). Dauert diese Entzündung über Jahre und Jahrzehnte an, kann es zu einer Zerstörung des normalen Lebergewebes und einem Umbau in eine Leberzirrhose kommen. Patienten mit einer chronischen Hepatitis C und einer Leberzirrhose haben ein deutlich erhöhtes Risiko, an Leberkrebs zu erkranken.

Unsere Forschungsgruppe beschäftigt sich mit der Immunantwort auf die Hepatitis C Virus Infektion, vor allem mit der sogenannten “angeborenen” Immunantwort (englisch: innate immune reaction). Bei dieser spielt das körpereigene Interferon eine entscheidende Rolle. Interferon wird aber auch als Medikament eingesetzt zur Behandlung der chronischen Hepatitis C. Bei unseren Untersuchungen haben wir festgestellt, dass der Erfolg einer Therapie mit Interferon ganz entscheidend davon abhängt, wie das angeborene Immunsystem vor der Therapie auf das Virus reagiert hat. Paradoxerweise sind dabei Patienten mit einer starken eigenen Immunantwort im Bezug auf das Therapieansprechen deutlich benachteiligt. Im Rahmen dieses Nationalfonds Gesuches werden wir untersuchen, wieso die angeborene Immunantwort so unterschiedlich stark ausfällt, und wieso Patienten mit einem starken Immunsystem nicht auf Interferontherapien reagieren. Wir erhoffen uns durch diese Forschung eine Verbesserung der Therapie für Patienten mit chronischer Hepatitis C.


Direct link to Lay Summary Last update: 27.03.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Quantitative proteomics and phosphoproteomics on serial tumor biopsies from a sorafenib-treated HCC patient.
Dazert Eva, Colombi Marco, Boldanova Tujana, Moes Suzette, Adametz David, Quagliata Luca, Roth Volker, Terracciano Luigi, Heim Markus H, Jenoe Paul, Hall Michael N (2016), Quantitative proteomics and phosphoproteomics on serial tumor biopsies from a sorafenib-treated HCC patient., in Proceedings of the National Academy of Sciences of the United States of America, 113(5), 1381-6.
YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors.
Marti Patricia, Stein Claudia, Blumer Tanja, Abraham Yann, Dill Michael T, Pikiolek Monika, Orsini Vanessa, Jurisic Giorgia, Megel Philippe, Makowska Zuzanna, Agarinis Claudia, Tornillo Luigi, Bouwmeester Tewis, Ruffner Heinz, Bauer Andreas, Parker Christian N, Schmelzle Tobias, Terracciano Luigi M, Heim Markus H, Tchorz Jan S (2015), YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors., in Hepatology (Baltimore, Md.), 62(5), 1497-510.
IFN-λ receptor 1 expression is induced in chronic hepatitis C and correlates with the IFN-λ3 genotype and with nonresponsiveness to IFN-α therapies.
Duong Francois H T, Trincucci Gaia, Boldanova Tujana, Calabrese Diego, Campana Benedetta, Krol Ilona, Durand Sarah C, Heydmann Laura, Zeisel Mirjam B, Baumert Thomas F, Heim Markus H (2014), IFN-λ receptor 1 expression is induced in chronic hepatitis C and correlates with the IFN-λ3 genotype and with nonresponsiveness to IFN-α therapies., in The Journal of experimental medicine, 211(5), 857-68.
Innate and adaptive immune responses in HCV infections.
Heim Markus H, Thimme Robert (2014), Innate and adaptive immune responses in HCV infections., in Journal of hepatology, 61(1 Suppl), 14-25.
Pegylated IFN-α regulates hepatic gene expression through transient Jak/STAT activation.
Dill Michael T, Makowska Zuzanna, Trincucci Gaia, Gruber Andreas J, Vogt Julia E, Filipowicz Magdalena, Calabrese Diego, Krol Ilona, Lau Daryl T, Terracciano Luigi, van Nimwegen Erik, Roth Volker, Heim Markus H (2014), Pegylated IFN-α regulates hepatic gene expression through transient Jak/STAT activation., in The Journal of clinical investigation, 124(4), 1568-81.
Protein phosphatase 2A promotes hepatocellular carcinogenesis in the diethylnitrosamine mouse model through inhibition of p53.
Duong François H T, Dill Michael T, Matter Matthias S, Makowska Zuzanna, Calabrese Diego, Dietsche Tanja, Ketterer Sylvia, Terracciano Luigi, Heim Markus H (2014), Protein phosphatase 2A promotes hepatocellular carcinogenesis in the diethylnitrosamine mouse model through inhibition of p53., in Carcinogenesis, 35(1), 114-22.
Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes.
Terczyńska-Dyla Ewa, Bibert Stephanie, Duong Francois H T, Krol Ilona, Jørgensen Sanne, Collinet Emilie, Kutalik Zoltán, Aubert Vincent, Cerny Andreas, Kaiser Laurent, Malinverni Raffaele, Mangia Alessandra, Moradpour Darius, Müllhaupt Beat, Negro Francesco, Santoro Rosanna, Semela David, Semmo Nasser, Heim Markus H, Bochud Pierre-Yves, Hartmann Rune (2014), Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes., in Nature communications, 5, 5699-5699.
Simultaneous detection of hepatitis C virus and interferon stimulated gene expression in infected human liver.
Wieland Stefan, Makowska Zuzanna, Campana Benedetta, Calabrese Diego, Dill Michael T, Chung Josan, Chisari Francis V, Heim Markus H (2014), Simultaneous detection of hepatitis C virus and interferon stimulated gene expression in infected human liver., in Hepatology (Baltimore, Md.), 59(6), 2121-30.
The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota.
Balmer Maria L, Slack Emma, de Gottardi Andrea, Lawson Melissa A E, Hapfelmeier Siegfried, Miele Luca, Grieco Antonio, Van Vlierberghe Hans, Fahrner René, Patuto Nicola, Bernsmeier Christine, Ronchi Francesca, Wyss Madeleine, Stroka Deborah, Dickgreber Nina, Heim Markus H, McCoy Kathy D, Macpherson Andrew J (2014), The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota., in Science translational medicine, 6(237), 237-66.
Vitamin D receptor and Jak-STAT signaling crosstalk results in calcitriol-mediated increase of hepatocellular response to IFN-α.
Lange Christian M, Gouttenoire Jérôme, Duong François H T, Morikawa Kenichi, Heim Markus H, Moradpour Darius (2014), Vitamin D receptor and Jak-STAT signaling crosstalk results in calcitriol-mediated increase of hepatocellular response to IFN-α., in Journal of immunology (Baltimore, Md. : 1950), 192(12), 6037-44.
25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end.
Heim Markus (2013), 25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end., in Nature Reviews Immunology, 535.
Innate immunity and HCV.
Heim Markus (2013), Innate immunity and HCV., in Journal of Hepatology, 564.
Protein phosphatase 2A promotes hepatocellular carcinogenesis in the diethylnitrosamine mouse model through inhibition of p53.
Duong François H T, Dill Michael T, Matter Matthias S, Makowska Zuzanna, Calabrese Diego, Dietsche Tanja, Ketterer Sylvia, Terracciano Luigi, Heim Markus H (2013), Protein phosphatase 2A promotes hepatocellular carcinogenesis in the diethylnitrosamine mouse model through inhibition of p53., in Carcinogenesis, 35(1), 114-22.
Sequential induction of type I and II interferons mediates a long-lasting gene induction in the liver in response to a novel toll-like receptor 9 agonist.
Makowska Zuzanna, Blumer Tanja, Duong François H T, La Monica Nicola, Kandimalla Ekambar R, Heim Markus H (2013), Sequential induction of type I and II interferons mediates a long-lasting gene induction in the liver in response to a novel toll-like receptor 9 agonist., in Journal of hepatology, 58(4), 743-9.

Collaboration

Group / person Country
Types of collaboration
Hall Michael, Biozentrum, Basel, Switzerland Switzerland (Europe)
- Publication
Volker Roth, Department of Mathematics and Informatics, Basel Switzerland (Europe)
- Publication
Frank Chisari/The Scripps Research Institute United States of America (North America)
- Publication
Luigi Terracciano, Pathology Institute Basel Switzerland (Europe)
- Publication
Darius Moradpour, CHUV, Lausanne Switzerland (Europe)
- Publication
Hartmann Rune, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denm Denmark (Europe)
- Publication
Bochud Pierre-Yves, Infectious Diseases Service, Department of Medicine, University Hospital and Uni Switzerland (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
The Liver Meeting 2013 Talk given at a conference Hepatic IFN lambda receptor 1 expression is induced in chronic hepatitis C and correlates with non-­‐response to IFN alpha and IL28B minor alleles 01.11.2013 Washington, United States of America Heim Markus;
The Liver Meeting Talk given at a conference Simultaneous detection of hepatitis C virus and interferon stimulated gene expression in infected human liver 01.11.2013 Washington, United States of America Heim Markus; Calabrese Diego; Makowska Zuzanna;
The International Liver Congress Talk given at a conference Innate immune responses and persistence of hepatitis C virus infection 27.04.2013 Amsterdam, Netherlands Heim Markus;


Associated projects

Number Title Start Funding scheme
130243 Interferon Signaling and Innate Immunity in Chronic Viral Hepatitis 01.04.2010 Project funding (Div. I-III)
166202 Interferon Regulated Immune Responses in Viral Hepatitis 01.04.2016 Project funding (Div. I-III)

Abstract

Chronic hepatitis C (CHC) is a major cause of chronic liver disease. An important and striking feature of hepatitis C virus (HCV) is its tendency toward chronicity. In > 70% of infected individuals, HCV establishes a persistent infection over decades that may lead to cirrhosis and hepatocellular carcinoma. This high rate of persistence is linked to an ability of HCV to evade and antagonize the immune response of the host. Type I interferons (IFNs) are crucial and potent components of the early host response against virus infection and recombinant pegylated IFNa (pegIFNa) in combination with ribavirin is the current standard therapy for CHC. About half of the patients can be cured.In the current BoE application, we plan to address several key points of the innate immune response to hepatitis C virus infection.1. Analysis of liver biopsies of HCV infected patients with a newly developed fluorescence in situ hybridization method (FISH).We will use a newly developed FISH method to visualize and quantify HCV RNA and mRNAs of IFNs and IFN stimulated genes in liver biopsies.2. IFNa induced signaling in the human liver.The pharmacodynamic effects of pegylated IFNa will be studied in liver biopsies obtained at different time points during the week after the first injection of pegylated IFNa in patients with CHC .3. The role of IFN? in establishing and maintaining IFN stimulated gene expression in the liver of HCV infected patients.We plan to systematically study IFN? and IFN? receptor expression in liver biopsies of patients with chronic hepatitis C (and controls) and correlate the status of the IFN? system with hepatic IFN stimulated gene expression. We will investigate the molecular mechanisms that links IL28B genotype with IFN stimulated gene expression and with non-response to pegIFN-a/ribavirin combination therapies.4. Functional characterization of IFNa induced long non-coding RNAs (lncRNAs)We have identified hundreds of lncRNAs that are induced by IFNa. We plan to study if some of them have a role in negative regulation of genes by IFNa.
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