Hepatology

Biography

Biography: Eve-Isabelle Pecheur

Abstract

Background & Aims: The hepatocyte microenvironment at the vicinity of cell surface (a.k.a. glycocalyx) is rich in membrane-anchored proteoglycans which are receptors for extracellular matrix proteins, cytokines, growth factors, lipoproteins and infectious agents. The hepatitis C virus (HCV) infects hepatocytes, after its initial attachment to the heparan sulfate proteoglycan syndecan-1. Here we investigated the link between the hepatocyte microenvironment, HCV entry and infection. Methods: Studies were carried out by RNA silencing, immunoprecipitation, proximity ligation assays, immunofluorescence and confocal imaging, coupled to cross-correlation and statistical analyses. Results: Hepatocyte infection by cell culture-grown HCV or clinical isolates was inhibited after knockdown of syndecan-1 or xylosyltransferase-2, a key enzyme of proteoglycan biosynthesis. Simultaneous knockdown of syndecan-1 and CD81, a receptor of HCV entry, strongly inhibited infection, suggesting their concerted action. At early infection stages, syndecan-1 and virions colocalized at the plasma membrane, and were internalized along with CD81 in endosomes. Direct interactions between syndecan-1 and CD81 were revealed in primary and transformed hepatocytes by immunoprecipitation and proximity ligation assays. This underpins the relevance of this interaction to HCV internalization and infection. Expression of syndecan-1 and xylosyltransferase-2 was altered within days post-infection, and the remaining syndecan-1 pool colocalized poorly with CD81. Conclusions: Syndecan-1 plays an important role in HCV entry and infection, and may act in concert with CD81, as syndecan-1 is detected in complex with CD81. Infection modulates syndecan-1 and xylosyltransferase-2 expression, underscoring a profound reshuffle of the hepatocyte glycocalyx early in infection, likely required for settling optimal conditions of viral propagation.