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Study of HBV and HDV transcriptomic modulation in HepaRG and PHHs

ABSTRACT: Chronic co-infection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. In this study, we aimed at elucidating the molecular mechanisms leading to the interference on HBV observed in most of patients co-infected with HDV. We performed transcriptomic analyses of in vitro samples in order to compare the HBV and HDV-induced modulations in viral transcription, immune response, and pathway regulation.This is of importance because beside providing basic knowledge on the interplay between a satellite virus and its helper virus, the data will help the identification of new antiviral target that may affect both viruses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE194179 | GEO | 2022/02/25

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.

Project description:Background and aims: The intrahepatic processes associated with chronic hepatitis B (CHB), especially in the context of HDV and HIV co-infection, require a better understanding. Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes, guiding new personalized treatments. Our aim is to evaluate this method to characterize the hepatic transcriptional landscape, cellular composition and biological pathways in liver biopsy samples from patients infected with HBV and HDV or HIV co-infection. Method: The GeoMx nanostring Digital Spatial Profiling (DSP) platform was employed to assess expression of HBsAg and CD45 in formalin fixed paraffin embedded (FFPE) biopsies from three treatment-naïve patients with chronic HBV and HDV or HIV co-infection. The GeoMx whole transcriptome human atlas assay quantified the expression of genes enriched in specific regions of interest (ROIs). Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas. A weighted gene correlation network analysis (WGCNA) evaluated transcriptomic signatures across sampled regions. Results: We identified spatially discrete transcriptomic signatures and distinct biological pathways that associate with HBV infection/disease status and immune responses. Shared features including cytotoxicity and B cell receptor signaling were consistent across patients, suggesting common elements alongside individual traits. HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment, whereas HIV/HBV co-infection featured genes related to interferon response regulation. Varied cellular characteristics and immune cell populations, with an abundance of T cells in the HDV/HBV sample, were observed within analyzed regions. Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression. Conclusion: This proof-of-principle study shows the value of this platform in investigating the complex immune landscape highlighting relevant host pathways to disease pathogenesis.

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Study of HBV and HDV transcriptomic modulation in HepaRG and PHHs

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