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Altérations du microenvironnement hépatocytaire suite à l'infection par le virus de l'hépatite C : implication dans la fibrogenèse hépatique précoce

Abstract : Hepatitis C is a chronic liver disease due to the infection by the hepatitis C virus (HCV), through exposure to contaminated blood. An estimated 3 to 4 million people are infected every year, with a viral prevalence rising up to 22% in the general population in Egypt. Over the past years, directacting antivirals (DAA) have emerged on the market, allowing a strong regression of the infection in developed countries. However these treatments are very expensive, and the underlying mechanisms of HCV infection remain ill-defined. HCV is an oncovirus, as are among others, the hepatitis B virus, human papilloma viruses, and herpes viruses. Contrary to those viruses, HCV does not seem to alter the genetic background of infected cells. Therefore, infectious mechanisms leading to cellular transformation are still unknown. HCV infects the epithelial cells of the liver, the hepatocytes. Infection leads to strong disruptions of glucide and lipid metabolism in these cells, contributing to HCV pathogenesis. Moreover HCV infection induces the accumulation of scarring tissue in the intercellular space of the liver, called fibrosis, which can evolve into cirrhosis with irreversible architectural and functional disorders. The ultimate step in hepatitis C progression is the development of an hepatocellular carcinoma (HCC) in 1-5% of cases, and many of these patients die the year following cancer diagnosis. We aimed at studying the early steps of viral pathogenesis, especially the establishment of liver fibrosis. This is the consequence of extracellular matrix (ECM) deposition in the intercellular space of the liver, fueled by both an oversecretion of ECM components and a lack of ECM degradation by specialized enzymes. The ECM is a complex compartment of the liver which controls molecular cellto- cell signaling. This greatly depends on what happens in the area situated right above the plasma membrane, called the cell coat or glycocalyx. This area mainly consists of proteoglycans, composed of a core protein on which long chains of sulfated sugars are anchored. These sugar chains are able to recognize and capture a myriad of signaling molecules in the ECM, in order to bring them closer to their receptors. Our first study demonstrated that one major proteoglycan was downregulated following HCV infection (Grigorov et al, 2017). We then decided to study on a more global scale how the glycocalyx evolved following this infection. Our work here is based on a multi-disciplinary approach combining molecular biology, biochemistry and cellular biology. We studied in details the glycocalyx components present at the surface of cells infected or not, as well as the expression of factors involved in their biosynthesis. This was first done in in vitro cellular models of infection, and extended where possible to biological samples from patients at various stages of chronic hepatitis. We observed a strong quantitative and qualitative reshuffling of the glycocalyx at the surface of infected cells, which correlated with major alterations in the biosynthesis of some proteoglycans. These abnormalities seemed to originate from the amount of a simple sugar, xylose, the main component of the biosynthesis of some proteoglycans. Indeed, intracellular concentrations of xylose were decreased in infected cells. This might bear a link to the observed alterations of a major signaling pathway controlling cell fate, which is partly regulated by xylose. This study sheds light on a previously unexplored aspect of HCV pathogenesis. Our results could contribute to explain the complications linked to this infection, since they underline major cellto- cell communication issues. Since most of the DAA-based therapies work badly once liver cirrhosis has settled, it could be interesting to combine antiviral treatments with anti-fibrotic agents in patients suffering from advanced hepatitis C
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Emma Reungoat. Altérations du microenvironnement hépatocytaire suite à l'infection par le virus de l'hépatite C : implication dans la fibrogenèse hépatique précoce. Virologie. Université de Lyon, 2018. Français. ⟨NNT : 2018LYSE1222⟩. ⟨tel-02028896⟩

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