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Interferon signaling in viral hepatitis

Trincucci, Gaia. Interferon signaling in viral hepatitis. 2013, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10370

Abstract

Hepatitis C virus (HCV) is a single stranded positive RNA virus classified in 6 different genotypes. Hepatocytes are the main targets of HCV infection. It has been estimated that 60 to 70% of the infected patients develop chronic infection. If left untreated, chronic hepatitis C (CHC) results in cirrhosis in 10 to 20% of the cases. Once cirrhosis is established, the risk of hepatocellular carcinoma (HCC) development increases dramatically, with an estimated annual rate of 1% to 4%. The standard of care (SOC) for CHC treatment is based on pegylated IFN? (peg-IFN?) and Ribavirin administration. Peg-IFN? injection activates the Jak-STAT signaling pathway that leads to the phosphorylation of STAT1 and culminates in the up-regulation of hundred of genes in the liver, establishing an antiviral state. However, peg-IFN?-based therapy achieves the clearance of HCV only in half of the chronic infected individuals. In the recent past, the lack of response to peg-IFN?-based therapy in CHC have been associated to the broad up-regulation of interferon regulated genes (IRGs) in the liver of CHC patients, already before treatment. The reason why the pre-activated hepatic IFN system fails to clear HCV remains to be elucidated. Furthermore, the molecular mechanisms that define the level of activation of the hepatic IFN system in CHC are not clear. In the recent past, several genome-wide association studies have reported a strong association of treatment-failure with minor (less frequent in the population) alleles at single nucleotide polymorphisms (SNPs) located in the IL28B locus on chromosome 19. Minor alleles at SNPs in the IL28B locus have also been associated to the up-regulation of the hepatic IFN system pre-treatment in CHC patients. So far the molecular mechanisms that links allelic variants at IL28B locus, the pre-activation of the hepatic IFN system and treatment-response in CHC patients remain to be elucidated. The present work is aimed to investigate two of the possible molecular mechanisms that could mediate the pre-activation of the IFN system in the liver of CHC patients that do not respond to therapy.
In the first part of the thesis the role of unphosphorylated-STAT1 (U-STAT1) in mediating the up-regulation of hepatic IRGs in CHC patients was investigated. We have reported that STAT1 accumulates in the liver of CHC patients non-responders. Furthermore, experimental evidences suggest that STAT1 could play a role as transcription factor independently by its phosphorylation on tyrosine 701 and its unphosphorylated form can drive the expression of a subset of IRGs. In the present study we took advantage of a cell line constitutively lacking STAT1 expression and we exogenously re-expressed a mutant form of STAT1 that can not be phosphorylated, mimicking U-STAT1. We proved that U-STAT1 per se is not able to induce the expression of IRGs and it is unlikely to be the cause of the pre-activated IFN system observed in the liver of non-responders CHC patients.
In the second part of the thesis, we investigated the role of IFN?s signaling pathway in the definition of the pre-activated hepatic IFN system in CHC. IFN?s are the most recently group of IFNs. IFN?s signal through the cells via a different receptor compared to the one of IFN?. However, the intracellular signaling pathway of the two class of cytokines is completely overlapping, leading to the up-regulation of the same IRGs. We demonstrated that in an hepatoma cell line Huh7 the over-expression of IL28R?, one of the two chains of INF? receptor complex, mediates the long lasting up-regulation of IRGs upon IFN? stimulation. We confirmed our results in human liver biopsies, where we found a significant positive correlation between IL28R? and IRGs expression. We observed that IL28R? is an IRG itself but its level of expression is modulated by allelic variants at SNPs mapping in the IL28B locus, that have been associated to treatment response in CHC patients.
In conclusion we provide evidences of a molecular mechanism that links the pre-activation of the hepatic IFN system (and non-response) and allelic variants at IL28B locus.
Advisors:-, -
Committee Members:Handschin, Christoph
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische F├Ącher (Klinik) > Hepatologie > Hepatologie (Heim)
Item Type:Thesis
Thesis no:10370
Bibsysno:Link to catalogue
Number of Pages:102 S.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:52
Deposited On:03 May 2013 14:50

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