Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA111329 | ENA |
REPOSITORIES: ENA
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Project description:Hepatitis C virus (HCV) infection is a global health problem. A number of studies have implicated a direct role of cellular lipid metabolism in the HCV life cycle and inhibitors of the mevalonate pathway have been demonstrated to result in an antiviral state within the host cell. Transcriptome profiling was also conducted on Huh-7 human hepatoma cells bearing subgenomic HCV replicons with and without treatment with 25-hydroxycholesterol (25-HC), an inhibitor of the mevalonate pathway that alters lipid metabolism, to assess metabolic determinants of pro- and antiviral states within the host cell. Experiment Overall Design: compound treatment and time course
2009-01-02 | E-GEOD-14204 | biostudies-arrayexpress
Project description:Hepatitis C virus (HCV) infection is a global health problem. A number of studies have implicated a direct role of cellular lipid metabolism in the HCV life cycle and inhibitors of the mevalonate pathway have been demonstrated to result in an antiviral state within the host cell. Transcriptome profiling was also conducted on Huh-7 human hepatoma cells bearing subgenomic HCV replicons with and without treatment with 25-hydroxycholesterol (25-HC), an inhibitor of the mevalonate pathway that alters lipid metabolism, to assess metabolic determinants of pro- and antiviral states within the host cell. Keywords: treatment and time course
2008-12-25 | GSE14204 | GEO
Project description:Our work demonstrated that 25-hydroxycholesterol induces the expression of miR-185, a microRNA which reinforces the oxysterol's antiviral effects on hepatic metabolism. We used microarrays to detail the effect of miR-185 on hepatic gene expression, and, within repressed genes, identified an enrichment for genes associated with cholesterol biosynthesis.
2015-10-19 | GSE73165 | GEO
Project description:Transcriptional profiling provides global snapshots of virus-mediated cellular reprogramming, which can simultaneously encompass pro- and antiviral components. To determine early transcriptional signatures associated with HCV infection of authentic target cells, we performed ex vivo infections of adult primary human hepatocytes (PHHs) from seven donors. Coordinated sampling identified minimal gene dysregulation at six hours post infection (hpi) in PHHs. In contrast, at 72 hpi, massive increases in the breadth and magnitude of HCV-induced gene dysregulation were apparent, affecting gene classes associated with diverse biological processes. Comparison with HCV-induced transcriptional dysregulation in Huh-7.5 cells identified limited overlap between the two systems. Of note, in PHHs, HCV infection initiated broad upregulation of canonical interferon (IFN)-mediated defense programs, limiting viral RNA replication and abrogating virion release. In addition, we confirm that constitutive expression of IRF1 in PHHs maintains a steady-state antiviral program in the absence of infection which can further reduce HCV RNA replication. We also detected infection-induced signatures of translational shutoff in PHHs - downregulation of ~90 genes encoding components of the EIF2 translation initiation complex and ribosomal subunits. As HCV polyprotein translation occurs independently of the EIF2 complex, this process is pro-viral: only translation initiation of host transcripts is arrested. The combination of antiviral intrinsic and inducible immunity, balanced against pro-viral programs, including translational arrest, maintains HCV replication at a low-level in PHHs. This may ultimately keep HCV under the radar of extra-hepatocyte immune surveillance while initial infection is established, promoting tolerance, preventing clearance and facilitating progression to chronicity.
2021-03-02 | GSE166428 | GEO
Project description:Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. HCV can be sensed by host innate immunity to induce expression of interferons (IFNs) and a number of antiviral effectors. HCV-encoded NS3/4 serine protease can subvert host innate immune responses by cleaving MAVS, a critical adaptor protein in the RLR-mediated IFN signaling. To study innate immunity in the context of HCV infection, we constructed Huh7-MAVSR cells which express a mutant MAVS resistant to NS3/4A cleavage. HCV infection induces robust IFN response in Huh7-MAVSR cells, providing a cellular system to study antiviral innate immune response against HCV infection. To analyze host innate antiviral effectors against HCV infection, we performed an mRNA microarray analysis in the HCV-infected Huh7-MAVSR cells.
2018-02-08 | GSE110312 | GEO
Project description:Background/Aim: Legalon SIL (SIL) is a chemically hydrophilized version of silibinin that has exhibited hepatoprotective and antiviral effectiveness against hepatitis C virus (HCV) in patients leading to viral clearance in combination with ribavirin. To elucidate the incompletely understood mode of action of SIL against HCV, we studied viral response kinetics and cellular gene expression during SIL treatment in the absence of an adaptive immune response in uPA-SCID chimeric mice with humanized livers. Methods: Chronically HCV-infected mice were treated with daily intravenous SIL at 469 mg/kg (n=5), 265 mg/kg (n=5) or 61.5 mg/kg (n=5). Serum HCV and human albumin (hAlb) were measured frequently and liver HCV RNA was analyzed at days 3 and 14. Microarray analysis of human hepatocyte gene expression was performed at days 0, 3, and 14 of treatment. Mathematical modeling was used to estimate viral kinetic parameters and SIL effectiveness. Results: While hAlb remained constant, a biphasic viral decline in serum was observed consisting of a rapid 1st phase followed by a 2nd slower (or plateau with the two lower SIL dosing) phase. SIL effectiveness in blocking viral production was similar among dosing groups (median =77%). However, the rate of HCV-infected hepatocyte decline, δ, was dose-dependent. Intracellular HCV RNA levels correlated (r=0.66, P=.01) with serum HCV RNA. Pathway analysis revealed increased anti-inflammatory and anti-proliferative gene expression in human hepatocytes in SIL-treated mice. Conclusions: The results suggest that SIL could lead to a continuous 2nd phase viral decline, i.e., potentially viral clearance, in the absence of adaptive immune response along with increased anti-inflammatory and anti-proliferative gene expression in human hepatocytes.
2017-04-01 | GSE79103 | GEO
Project description:Hepatitis C virus (HCV) infection constitutes a global health problem with 71 million people currently chronically infected. Recent studies have reported that C19orf66 is expressed as an interferon (IFN)-stimulated gene; however, the intrinsic regulation of this gene within the liver as well as its antiviral effects against HCV remains elusive. In this study, we observed an upregulation of C19orf66 in vivo and ex vivo in response to HCV infection and to IFN therapy. Expression of C19orf66 restricted HCV infection, whereas CRIPSPR/Cas9 mediated knockout of C19orf66 attenuated IFN-mediated suppression of HCV replication. Co-immunoprecipitation followed by mass spectrometry identified a stress granule dominated interactome of C19orf66. Mechanistic studies revealed that C19orf66 expression impairs HCV-induced elevation of PI(4)P and alters the morphology of the viral replication organelle, designated membranous web, thus suppressing viral RNA replication. Collectively, our data suggest that C19orf66 contributes to the innate immune response against HCV in the liver.
2020-02-28 | GSE146075 | GEO
Project description:Host cells harbor various intrinsic mechanisms to restrict viral infections as a first line of antiviral defense. Viruses have evolved various countermeasures against these antiviral mechanisms. Here we show that N-Myc Downstream-Reguated Gene 1 (NDRG1) limits productive HCV infection by inhibiting viral assembly. Interestingly, HCV infection down-regulates NDRG1 protein and mRNA expression. Loss of NDRG1 increases the size and number of lipid droplets, which are the sites of HCV assembly. HCV suppresses NDRG1 expression by up-regulating MYC, which directly inhibits the transcription of NDRG1. Up-regulation of MYC also leads to reduced expression of NDRG1-specific kinase SGK1, resulting in markedly diminished phosphorylation of NDRG1. Knockdown of MYC during HCV infection rescues NDRG1 expression and phosphorylation, suggesting that MYC regulates NDRG1 at both transcriptional and post-translational levels. Overall, our results suggest that NDRG1 restricts HCV assembly by limiting lipid droplet formation. HCV counteracts this intrinsic antiviral mechanism by down-regulating NDRG1 via a MYC-dependent mechanism.
2017-11-17 | GSE106988 | GEO
Project description:25-hydroxycholesterol has been demonstrated to regulate SREBP processing, yet Ch25h-deficient mice have no cholesterol abnormalities. Using RNA-seq, we find that LPS-stimulated, Ch25h-deficient BMDMs have dysregulated SREBP target genes, demonstrating that 25-hydroxycholesterol is an induced repressor of SREBP during inflammatory settings.
2014-08-08 | GSE58993 | GEO
Project description:Background and aims: Hepatitis C virus (HCV) infection is a major cause of liver disease including steatosis, fibrosis and liver cancer. Viral cure cannot fully eliminate the risk of disease progression and hepatocellular carcinoma (HCC) in advanced liver disease. The mechanisms for establishment of infection, liver disease progression and hepatocarcinogenesis are only partially understood. To address these questions, we probed the functional proteogenomic architecture of HCV infection within a hepatocyte-model. Methods: Time-resolved HCV infection of hepatocyte-like cells was analyzed by RNA sequencing, proteomics, metabolomics, and leveraged by integrative genomic analyses. Using differential expression, gene set enrichment analyses, and protein-protein interaction mapping we identified pathways relevant for liver disease pathogenesis that we validated in livers of 216 cirrhotic patients with HCV. Results: We uncovered marked changes in the protein expression of gene sets involved in innate immunity, metabolism and hepatocarcinogenesis. In infected cells, HCV enhances glucose metabolism and creates a Warburg-like shift of the lactate flux. HCV infection impaired the formation of peroxisomes -organelles required for long-chain fatty acid oxidation- causing intracellular fatty acid accumulation, which is a hallmark of non-alcoholic fatty liver disease (NAFLD). Ex vivo studies confirmed perturbed peroxisomes and revealed an association of hepatic catalase expression with clinical outcomes and phenotypes in HCV-associated cirrhosis, NAFLD and HCC cohorts. Conclusion: Our integrative analyses uncover how HCV perturbs the hepatocyte cell circuits to drive chronic liver disease and hepatocarcinogenesis. This proteogenomic atlas of HCV infection provides a model for the discovery of novel drivers for viral- and non-viral induced liver disease.
2019-04-17 | GSE126831 | GEO