Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Hepatitis C Core Protein Induces a Genotype-specific Susceptibility of Hepatocytes to TNF-induced Death in vitro and in vivo

Savvina Moustafa
ORCID logo ,
Katerina Kassela
,
Maria Bampali
,
Nikolas Dovrolis
ORCID logo ,
Athanassios Kakkanas
,
Apostolos Beloukas
* ORCID logo ,
Penelope Mavromara
,
Ioannis Karakasiliotis
* ORCID logo
Version 1 : Received: 21 August 2022 / Approved: 6 September 2022 / Online: 6 September 2022 (03:38:14 CEST)

A peer-reviewed article of this Preprint also exists.

Moustafa, S.; Kassela, K.; Bampali, M.; Dovrolis, N.; Kakkanas, A.; Beloukas, A.; Mavromara, P.; Karakasiliotis, I. Hepatitis C Core Protein Induces a Genotype-Specific Susceptibility of Hepatocytes to TNF-Induced Death In Vitro and In Vivo. Viruses 2022, 14, 2521. Moustafa, S.; Kassela, K.; Bampali, M.; Dovrolis, N.; Kakkanas, A.; Beloukas, A.; Mavromara, P.; Karakasiliotis, I. Hepatitis C Core Protein Induces a Genotype-Specific Susceptibility of Hepatocytes to TNF-Induced Death In Vitro and In Vivo. Viruses 2022, 14, 2521.

Abstract

Hepatitis C virus (HCV) core protein is a multifunctional protein that is involved in proliferation, inflammation and apoptosis mechanism of hepatocytes. HCV core protein genetic variability has been implicated in various outcomes of HCV pathology and treatment. In the present study, we aimed to analyze the role of HCV core protein in tumor necrosis factor α (TNFα)-induced death under the viewpoint of HCV genetic variability. Immortalized hepatocytes (IHH), and not the Huh7.5 hepatoma cell line, stably expressing HCV subtype 4a and HCV subtype 4f core proteins showed that only HCV 4a core protein could increase sensitivity to TNFα-induced death. Development of two transgenic mice expressing the two different core proteins under the liver-specific promoter of transthyretin (TTR) allowed for the in vivo assessment of the role of core in TNFα-induced death. Using the TNFα-dependent model of lipopolysaccharide/D-galactosamine (LPS/Dgal) we were able to recapitulate the in vitro results in IHH cells in vivo. Transgenic mice expressing HCV 4a core protein were more susceptible to the LPS/Dgal model while mice expressing HCV 4f core protein had the same susceptibility as their littermate controls. Transcriptome analysis in liver biopsies from these transgenic mice gave insights into HCV core molecular pathogenesis, while linking HCV core protein genetic variability to differential pathology in vivo.

Keywords

Hepatitis C virus; core protein; TNFα

Subject

Medicine and Pharmacology, Pathology and Pathobiology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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