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Comparative analysis of gene expression upon DMSO-induced differentiation of hepatoma cell lines [Dif]

ABSTRACT: The liver, and more precisely hepatocytes, can be infected by several viruses such as hepatitis B (HBV), hepatitis D (HDV), hepatitis C (HCV), hepatitis E (HEV) viruses, with chronic infection leading to end-stage liver diseases. Since no in vitro model allowing multi-infections with the four viruses is reported, limited data are available on the interplay between those viruses as well as on the potential cross-reactivity of antivirals in multi-infection cases. Here we showed that HuH7.5-NTCP cells can be partially differentiated into hepatocyte-like cells and genuinely replicate HBV, HDV, HCV and HEV for at least 4 weeks after mono or multiple infections. Additionally, we recapitulated the effect of known antivirals and found that FXR-agonists, also strongly inhibited HEV replication. Using HEV infected HuHep mice, we confirmed the antiviral effect of Vonafexor, the FXR agonist clinical candidate currently tested against HBV and HDV, highlighting FXR-ligands as potential broad acting antivirals. Here, we set-up the first in vitro model allowing multi-infections with hepatitis viruses that can be used for broad drug screening.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288204 | GEO | 2025/04/23

REPOSITORIES: GEO

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Project description:The same entry pathway is shared by HBV and HDV. Both viruses attach to hepatocytes via heparansulfate proteoglycan and utilize sodium taurocholate co-transporting polypeptide (NTCP) for a specifc entry. This specific entry step is inhibited by Myrcludex B, a 47-aa lipopeptide myristoylated at the N-terminus. Here we compared the cellular response in the gene expression level triggerred by both viruses. The microarray data shows that HBV infection leads to a silent response but HDV infection triggers high level of innate response such as inteferon-stimulated genes (ISG) expression. Moreover, the response depends on the hepatic cell lines used for infection. Compared to HepG2 cells, HuH7 can not induce ISG even infected by HDV. Abstract of manuscript: Background & aims: Hepatitis B virus (HBV) and D virus (HDV) co-infections cause the most severe form of viral hepatitis. HDV induces an innate immune response, but it is unknown how the host cell senses HDV and if this defense affects HDV replication. We aim to characterize interferon (IFN) activation by HDV, identify the responsible sensor and evaluate the effect of IFN on HDV replication. Methods: HDV and HBV susceptible hepatoma cell lines and primary human hepatocytes (PHH) were used for infection studies. Viral markers and cellular gene expression were analyzed at different time points after infection. Pattern recognition receptors (PRRs) required for HDV-mediated IFN activation and the impact on HDV replication were studied using stable knock-down or overexpression of the PRRs. Results: Microarray analysis revealed that HDV but not HBV infection activated a broad range of interferon stimulated genes (ISGs) in HepG2NTCP cells. HDV strongly activated IFN-β and IFN-λ in cell lines and PHH. HDV induced IFN levels remained unaltered upon RIG-I or TLR3 knock-down, but were almost completely abolished upon MDA5 depletion. Conversely, overexpression of MDA5 but not RIG-I and TLR3 in Huh7.5NTCP cells partially restored ISG induction. During long-term infection, IFN levels gradually diminished in both HepG2NTCP and HepaRGNTCP cell lines. MDA5 depletion had little effect on HDV replication despite dampening HDV-induced IFN response. Moreover, treatment with type I or type III IFNs did not abolish HDV replication. Conclusions: Active replication of HDV induces an IFN-β/λ response, which is predominantly mediated by MDA5. This IFN response and exogenous IFN treatment have only a moderate effect on HDV replication in vitro indicating the adaption of HDV replication to an IFN activated state.

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Comparative analysis of gene expression upon DMSO-induced differentiation of hepatoma cell lines [Dif]

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