Robust hepatitis E virus infection and transcriptional response in human hepatocytes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA559467 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9937550_1.fastq.gz | Fastqsanger.gz | |||
| SRR9937550_2.fastq.gz | Fastqsanger.gz | |||
| SRR9937560_1.fastq.gz | Fastqsanger.gz | |||
| SRR9937560_2.fastq.gz | Fastqsanger.gz | |||
| SRR9937570_1.fastq.gz | Fastqsanger.gz |
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Project description:Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and the leading cause for acute viral hepatitis worldwide. The virus is classified as a member of the genus Orthohepevirus A within the Hepeviridae family. Due to the absence of a robust cell culture model for HEV infection, the analysis of the viral life cycle, the development of effective antivirals and a vaccine is severely limited. In this study, we established a protocol based on the HEV genotype 3 p6 (Kernow C-1) and the human hepatoma cell lines HepG2 and HepG2/C3A with different media conditions to produce intracellular HEV cell culture-derived particles (HEVcc) with viral titers between 105 and 106 FFU/mL. Viral titers could be further enhanced by an HEV variant harboring a mutation in the RNA-dependent RNA polymerase. These HEVcc particles were characterized in density gradients and allowed the trans-complementation of subgenomic reporter HEV replicons. In addition, in vitro produced intracellular-derived particles were infectious in liver-humanized mice with high RNA copy numbers detectable in serum and feces. Efficient infection of primary human and swine hepatocytes using the developed protocol could be observed and was inhibited by ribavirin. Finally, RNA sequencing studies of HEV-infected primary human hepatocytes demonstrated a temporally structured transcriptional defense response. In conclusion, this robust cell culture model of HEV infection provides a powerful tool for studying viral-host interactions that should facilitate the discovery of antiviral drugs for this important zoonotic pathogen.
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Project description:Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders.
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Project description:Phosphorylation is a major post-translation modification (PTM) of proteins, and small molecules, which is finely tuned by the activity of several hundred kinases and phosphatases. It controls most if not all cellular pathways including anti-viral responses. Accordingly, viruses often induce important changes in the phosphorylation of host factors that can either help or counteract viral replication. Surprisingly, among more than 500 kinases constituting the human kinome only few have been described as important for the Hepatitis B virus (HBV) infectious cycle, and most of them intervene during early or late infectious steps by phosphorylating the viral Core protein (HBc) protein. In addition, scarce information is available on the consequences of HBV infection on the activity of cellular kinases. The objective of this study was to investigate the global impact of HBV infection on the cellular phosphorylation landscape at early after infection. For this, primary human hepatocytes (PHH) were challenged or not with HBV, and a mass spectrometry (MS)-based quantitative phospho-proteomic analysis was conducted two- and seven-days post-infection.
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Project description:Background: Human hepatitis E virus (HEV) usually causes a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic and severe course of infection. Janus kinase (JAK) inhibitors (JAKi) are a novel drug class for the treatment of autoimmune inflammatory rheumatic disease (AIRD). As JAKs play a key role in innate immunity, viral infections and reactivations are frequently reported during JAKi treatment in AIRD patients. The aim of this study was to characterize the influence of JAKis on HEV replication in vivo and in authentic cell culture models ex vivo. Methods: We evaluated liver enzymes of an AIRD patient under JAKi therapy with hepatitis E and HEV infections in a cohort of AIRD patients. Experiments with HEV were performed by infection of primary human hepatocytes (PHHs) followed by immunofluorescence staining of viral markers and transcriptomic analysis. Results: Acute hepatitis was observed in a patient with AIRD and concomitant HEV infection. No acute infection could be detected in the AIRD cohort. Infection experiments in PHHs displayed an up to 50-fold increase of progeny virus production during JAKi treatment and transcriptomic analysis revealed induction of antiviral programs during infection. This induction was perturbed in the presence of JAKis, concomitant with elevated HEV RNA levels. Conclusion: Therapeutic JAK inhibition increases HEV replication by modulating the HEV-triggered immune response. Therefore, clinical monitoring of HEV infection during JAKi treatment and in case of elevated liver enzymes should be considered.
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Project description:Global temporal quantitative proteomic and transcriptomic analysis using long-term hepatitis B virus (HBV)-infected primary human hepatocytes uncovered extensive remodeling of host proteome and transcriptome, and revealed cytopathic effects of long-term viral replication. Metabolic-, complement-, cytoskeleton-, mitochondrial- and oxidation-related pathways were modulated at transcriptional or post-transcriptional levels, which could be partially rescued by early rather than late nucleot(s)ide analogs (NAs) therapy. Overexpression screening identified a series of pro- or anti- HBV host factors. These data have deepened the understanding of the mechanisms of viral pathogenesis and HBV-host interactions in hepatocytes, with implications for therapeutic intervention.
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Project description:The natural history of chronic hepatitis B virus (HBV) infection could be divided in different phases by transaminase and HBV replication levels. However, it remains unknown how the intrahepatic transcriptomes in patients are correlated with the clinical phases. Here, we determined the intrahepatic transcriptomes of chronic hepatitis B patients and examined the role of specific groups of genes, including immune-related genes, in the control of hepatitis B virus infection.
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Project description:Objective: Antigen-specific immunotherapy is a promising strategy to treat hepatitis B virus (HBV) infection and (HBV-related) hepatocellular carcinoma (HCC). To facilitate killing of malignant and/or infected hepatocytes, it is vital to know which T cell targets are presented by HLA-I complexes on patient-derived hepatocytes. Here, we aimed to reveal the hepatocyte-specific HLA-I peptidome with emphasis on peptides derived from HBV proteins and tumor associated antigens (TAAs) to guide development of antigen-specific immunotherapy. Design: Primary human hepatocytes were isolated with high purity from (HBV infected) non-tumor and HCC tissues using a newly designed perfusion-free procedure. Subsequently, hepatocyte-derived HLA-bound peptides were identified by mass spectrometry after which source proteins were subjected to gene ontology and pathway analysis. Finally, all HBV-antigen and TAA-derived HLA-peptides were extracted and a selection was tested for immunogenicity. Results: We acquired a high quality HLA-I peptidome of 2x105 peptides, of which source proteins were associated with hepatocyte function. Importantly, we demonstrated HLA-I presentation of HBV-derived and TAA-derived peptides for the first time in immune cell-depleted primary liver cell isolates. The peptidome included 8 HBV-derived peptides and 14 peptides from 8 known HCC-associated TAAs that were exclusively identified in tumor eluates. Of these, immunogenicity was demonstrated for 5 HBV-derived and 3 TAA-derived peptides. Conclusion: We present a first HLA-I immunopeptidome of isolated primary human hepatocytes, devoid of immune cells. Our results directly aid development of antigen-specific immunotherapy for HBV infection and HCC. Described methodology can also be applied to personalize immunotherapeutic treatment of liver diseases in the future.
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