Gene expression profile at single cell level of human peripheral blood mononuclear cells cocultured with rotavirus treated or PBS treated human cholangiocyte cell line H69.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE225177 | GEO | 2024/05/15
REPOSITORIES: GEO
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Project description:Biliary atresia (BA) is the leading indication for pediatric liver transplantation. Rhesus rotavirus (RRV) induced murine BA develops an obstructive cholangiopathy that mirrors the human disease. We have previously demonstrated the "SRL" motif on RRV's VP4 protein binds to heat shock cognate 70 protein (Hsc70) facilitating entry into cholangiocytes. In this study, we analyzed how binding to Hsc70 affects viral endocytosis, intracellular trafficking, and uniquely activates the signaling pathway that induces murine BA. Inhibition of clathrin- and dynamin-mediated endocytosis in cholangiocytes following infection demonstrated blocking dynamin decreased the infectivity of RRV whereas clathrin inhibition had no eaffect. Blocking early endosome trafficking resulted in decreased viral titers of RRV while late endosome inhibition had no effect. Following infection, p-NF-?B levels and TLR3 expression increased in cholangiocytes, leading to increased release of CXCL9 and CXCL10. Infected mice knocked out for TLR3 had decreased levels of CXLC9 and CXCL10, resulting in reduced NK cell numbers. Human BA patients experienced an increase in CXCL10 levels, suggesting this as a possible pathway leading to biliary obstruction. Viruses that utilize Hsc70 for cell entry exploit a chlathrin-independent pathway and traffic to the early recycling endosome uniquely activating NF-kB through TLR3, releasing leading to the release of CXCL9 and CXCL10, and inducing NK cell recruitment. These results define how the "SRL" peptide found on RRV's VP4 protein modulates viral trafficking, inducing the host response leading to bile duct obstruction.
2024-05-29 | GSE267721 | GEO
Project description:A recent multicenter genetic exploration of the biliary atresia splenic malformation (BASM) syndrome identified mutations in the ciliary gene PKD1L1 as candidate etiologic contributors. We hypothesized that deletion of Pkd1l1 in hepatoblasts would provide a mouse model of the developmental cholangiopathy of BA. We then performed gene expression profiling analysis using data obtained from total RNA-seq, isolated from the livers of Pkd1l1Fl/Fl (Fl/Fl) and Pkd1l1Fl/Fl x AFP-CRE mice (Pkd1l1ΔExon8/ΔExon8 Liver knockout ; LKO) at 7 weeks.
2023-01-20 | GSE201330 | GEO
Project description:We characterize three subpopulations of cholestatic macrophages in pediatric patients with biliary atresia (BA) and Alagille syndrome (ALGS).
2020-12-22 | GSE163650 | GEO
Project description:Biliary atresia (BA) is a progressive fibro-inflammatory disorder that is the leading indication for liver transplantation in children. Although there is evidence implicating genetic, infectious, environmental, and inflammatory causes, the etiology of BA remains unknown. We have recently reported that cholangiocytes from BA patients showed decreased DNA methylation relative to disease- and non-disease controls, supporting a potential role for DNA hypomethylation in BA etiopathogenesis.
2015-06-18 | GSE69948 | GEO
Project description:<p>Maternal seeding of the microbiome in neonates promotes a long-lasting biological footprint, but how it impacts disease susceptibility in early life remains unknown. We hypothesized that feeding butyrate to pregnant mice influences the newborn’s susceptibility to biliary atresia, a severe cholangiopathy of neonates. Here, we show that butyrate administration to mothers renders newborn mice resistant to inflammation and injury of bile ducts and improves survival. The prevention of hepatic immune cell activation and survival trait is linked to fecal signatures of Bacteroidetes and Clostridia and increases glutamate/glutamine and hypoxanthine in stool metabolites of newborn mice. In human neonates with biliary atresia, the fecal microbiome signature of these bacteria is under-represented, with suppression of glutamate/glutamine and increased hypoxanthine pathways. The direct administration of butyrate or glutamine to newborn mice attenuates the disease phenotype, but only glutamine renders bile duct epithelial cells resistant to cytotoxicity by natural killer cells. Thus, maternal intake of butyrate influences the fecal microbial population and metabolites in newborn mice and the phenotypic expression of experimental biliary atresia, with glutamine promoting survival of bile duct epithelial cells.</p>
2022-01-11 | MTBLS2171 | MetaboLights
Project description:Ischemic cholangiopathy refers to biliary damage caused by disruption of blood supply in the peribiliary plexus. Detailed knowledge of ischemic cholangiopathy pathogenesis remains scarce due to the lack of appropriate in vitro models. We aimed to recapitulate ischemia-evoked biliary damage using human intrahepatic cholangiocyte organoids (ICOs) in vitro for the study of ischemic cholangiopathy and preclinical drug discovery. In our study, we found that ICOs can recapitulate ischemic cholangiopathy in vitro, featured by extensive apoptosis and reduced cell proliferation, which could be partially restored by reoxygenation. AAT is identified as a novel cholangiocellular protective agent by restoring proliferation and preventing apoptosis.
2022-11-01 | GSE198860 | GEO
Project description:Objective of the study is to determine global changes in gene expression after HDAC inhibitor Trichostatin (TSA) treatment in H69 cell line
2021-05-26 | GSE161313 | GEO
Project description:Biliary atresia (BA) is a rare cholestatic disease of unknown etiology that affects infants and shows an incidence of 1 out of 18,000 live births in Europe (1). The first therapeutic option is a timely performed portoenterostomy. However, the majority of patients suffer from a progressive inflammatory process, which leads to complete destruction of the extra- and intrahepatic biliary system followed by end-stage liver cirrhosis. Hence, BA is the leading indication for pediatric liver transplantation worldwide (2, 3). To understand the pathogenesis of the disease and improve theoutcome of BA patients, research has focused on the inflammatory process in liver and bile ducts, in which several factors are remarkably elevated, such as activated CD4 and CD8 T-cells, TNF alpha,IFN alpha and other proinflammatory TH1 cytokines (3-8). By the time of diagnosis, however, the disease has already reached an advanced state, characterized by the complete obstruction of the extrahepatic bile ducts with impaired bile flow and fibrosis or cirrhosis of the liver. Therefore, studies in humans focusing on the trigger mechanism of BA are limited due to the paucity of liver and availability of bile duct tissue for research. One infectious animal model has been developed, in which newborn Balb/c mice exclusively show the experimental BA phenotype after infection with rhesus rotavirus (RRV) (9, 10). This model allows the analysis of the inflammatory reactions in liver and bile ducts at early steps in the development of bile duct atresia (11-20). Furthermore, inbred mouse strains have been shown to have a different susceptibility for the development of experimental BA, suggesting that Balb/c mice have an immunological gap responsible for disease progression (10, 12). The aim of this study was to identify key genes responsible for the BA phenotype by comparing the transcriptomes at an early time point after virus infection, i.e. before bile duct atresia, between two mouse strains with different susceptibilities to BA. Differences in the virus titration and the clinical course of infected mice were analyzed, and variations in the hepatic gene response assessed by comparative microarray assays were correlated to variances in the hepatic inflammatory reaction. Balb/c mice and C57Black/6 (Black/6) mice were infected with RRV postpartum and signs of BA and survival were noted. Liver sections of diseased, healthy and control animals were assessed for T-cell expression, and the virus loads were determined. Second, mice were sacrificed after three days, and isolated hepatic RNA was subjected to gene expression analysis using Affymetrix Gene Chip MOE 430 2.0.We compared three individual expression profiles from RRV-infected Balb/c mice against 2 individual expression profiles from RRV-infected C57/BL6 control mice using the Affymetrix GeneChip MOE 430 2.0.
2009-08-30 | E-GEOD-13245 | biostudies-arrayexpress
Project description:Early diagnosis of biliary atresia (BA) is crucial for improving the chances of survival and preserving the liver function of children with BA. To explore potential biomarkers for early diagnosis of BA with other non-BA jaundice cases, we performed proteomic analysis with data-independent acquisition (DIA) and parallel reaction monitoring (PRM). With this approach we were able to detect and validate differential protein expression in plasma of patients. Bioinformatics analysis revealed the enrichment biological processes, characteristic of BA by identifying differential expression of specific proteins of which with 10 were up- and 23 down-regulated. Signaling pathway analysis demonstrated changes in protein expression associated with an alteration in immunoglobins levels, which is indicative immune dysfunction in BA. When polymeric immunoglobulin receptor (pIgR) expression was combined with an immunoglobulin lambda variable chain (IGL c2225_light_IGLV1-47_IGLJ2), revealed by machine learning, they provided a useful early diagnostic model for BA, which had a sensitivity of 0.8, specificity of 1, accuracy of 0.89, and AUC value of 0.944. Our study not only identified a possible effective plasma biomarker for the early diagnosis of BA but may also help to further elucidate the underlying mechanisms of BA.
2024-06-22 | PXD048938 | Pride
Project description:Biliary atresia (BA) is a rare cholestatic disease of unknown etiology that affects infants and shows an incidence of 1 out of 18,000 live births in Europe (1). The first therapeutic option is a timely performed portoenterostomy. However, the majority of patients suffer from a progressive inflammatory process, which leads to complete destruction of the extra- and intrahepatic biliary system followed by end-stage liver cirrhosis. Hence, BA is the leading indication for pediatric liver transplantation worldwide (2, 3). To understand the pathogenesis of the disease and improve theoutcome of BA patients, research has focused on the inflammatory process in liver and bile ducts, in which several factors are remarkably elevated, such as activated CD4 and CD8 T-cells, TNF alpha,IFN alpha and other proinflammatory TH1 cytokines (3-8). By the time of diagnosis, however, the disease has already reached an advanced state, characterized by the complete obstruction of the extrahepatic bile ducts with impaired bile flow and fibrosis or cirrhosis of the liver. Therefore, studies in humans focusing on the trigger mechanism of BA are limited due to the paucity of liver and availability of bile duct tissue for research. One infectious animal model has been developed, in which newborn Balb/c mice exclusively show the experimental BA phenotype after infection with rhesus rotavirus (RRV) (9, 10). This model allows the analysis of the inflammatory reactions in liver and bile ducts at early steps in the development of bile duct atresia (11-20). Furthermore, inbred mouse strains have been shown to have a different susceptibility for the development of experimental BA, suggesting that Balb/c mice have an immunological gap responsible for disease progression (10, 12). The aim of this study was to identify key genes responsible for the BA phenotype by comparing the transcriptomes at an early time point after virus infection, i.e. before bile duct atresia, between two mouse strains with different susceptibilities to BA. Differences in the virus titration and the clinical course of infected mice were analyzed, and variations in the hepatic gene response assessed by comparative microarray assays were correlated to variances in the hepatic inflammatory reaction.
2009-08-30 | GSE13245 | GEO