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Role of viruses in biliary atresia: news from mice and men.

ABSTRACT: Biliary atresia (BA) is still an enigmatic disease of unknown etiology and cryptic pathomechanism. Despite the fact that BA is rated among rare diseases, it represents the most frequent indication for pediatric liver transplantation. Although every effort is made to elucidate the origin of the ongoing deterioration of liver function, no breakthrough has so far been achieved, which switches the surgical but symptomatic therapy to a cause-oriented approach. The nowadays leading hypothesis focuses on hepatotropic virus as a triggering agent for an autoimmunological self-limiting inflammatory process along the entire biliary tree. The present review highlights the current state of research on the factor "viruses in biliary atresia" in both patients undergoing the Kasai procedure and the virus-induced BA mouse model.

SUBMITTER: Petersen C

PROVIDER: S-EPMC6604572 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Role of viruses in biliary atresia: news from mice and men.

Petersen Claus C Madadi-Sanjani Omid O

Innovative surgical sciences 20180404 2

Biliary atresia (BA) is still an enigmatic disease of unknown etiology and cryptic pathomechanism. Despite the fact that BA is rated among rare diseases, it represents the most frequent indication for pediatric liver transplantation. Although every effort is made to elucidate the origin of the ongoing deterioration of liver function, no breakthrough has so far been achieved, which switches the surgical but symptomatic therapy to a cause-oriented approach. The nowadays leading hypothesis focuses ...[more]

PMID: 31579773

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Project description:Altered extrahepatic bile ducts, gut, and cardiovascular anomalies constitute the variable phenotype of biliary atresia (BA).To identify potential susceptibility loci, Caucasian children, normal (controls) and with BA (cases) at two US centers were compared at >550000 SNP loci. Systems biology analysis was carried out on the data. In order to validate a key gene identified in the analysis, biliary morphogenesis was evaluated in 2-5-day post-fertilization zebrafish embryos after morpholino-antisense oligonucleotide knockdown of the candidate gene ADP ribosylation factor-6 (ARF6, Mo-arf6).Among 39 and 24 cases at centers 1 and 2, respectively, and 1907 controls, which clustered together on principal component analysis, the SNPs rs3126184 and rs10140366 in a 3' flanking enhancer region for ARF6 demonstrated higher minor allele frequencies (MAF) in each cohort, and 63 combined cases, compared with controls (0.286 vs. 0.131, P = 5.94x10-7, OR 2.66; 0.286 vs. 0.13, P = 5.57x10-7, OR 2.66). Significance was enhanced in 77 total cases, which included 14 additional BA genotyped at rs3126184 only (p = 1.58x10-2, OR = 2.66). Pathway analysis of the 1000 top-ranked SNPs in CHP cases revealed enrichment of genes for EGF regulators (p<1 x10-7), ERK/MAPK and CREB canonical pathways (p<1 x10-34), and functional networks for cellular development and proliferation (p<1 x10-45), further supporting the role of EGFR-ARF6 signaling in BA. In zebrafish embryos, Mo-arf6 injection resulted in a sparse intrahepatic biliary network, several biliary epithelial cell defects, and poor bile excretion to the gall bladder compared with uninjected embryos. Biliary defects were reproduced with the EGFR-blocker AG1478 alone or with Mo-arf6 at lower doses of each agent and rescued with arf6 mRNA.The BA-associated SNPs identify a chromosome 14q21.3 susceptibility locus encompassing the ARF6 gene. arf6 knockdown in zebrafish implicates early biliary dysgenesis as a basis for BA, and also suggests a role for EGFR signaling in BA pathogenesis.

Project description:Biliary atresia (BA) is notable for marked ductular reaction and rapid development of fibrosis. Activation of the Hedgehog (Hh) pathway promotes the expansion of populations of immature epithelial cells that coexpress mesenchymal markers and may be profibrogenic. We examined the hypothesis that in BA excessive Hh activation impedes ductular morphogenesis and enhances fibrogenesis by promoting accumulation of immature ductular cells with a mesenchymal phenotype. Livers and remnant extrahepatic ducts from BA patients were evaluated by quantitative reverse-transcription polymerase chain reaction (QRT-PCR) and immunostaining for Hh ligands, target genes, and markers of mesenchymal cells or ductular progenitors. Findings were compared to children with genetic cholestatic disease, age-matched deceased donor controls, and adult controls. Ductular cells isolated from adult rats with and without bile duct ligation were incubated with Hh ligand-enriched medium ± Hh-neutralizing antibody to determine direct effects of Hh ligands on epithelial to mesenchymal transition (EMT) marker expression. Livers from pediatric controls showed greater innate Hh activation than adult controls. In children with BA, both intra- and extrahepatic ductular cells demonstrated striking up-regulation of Hh ligand production and increased expression of Hh target genes. Excessive accumulation of Hh-producing cells and Hh-responsive cells also occurred in other infantile cholestatic diseases. Further analysis of the BA samples demonstrated that immature ductular cells with a mesenchymal phenotype were Hh-responsive. Treating immature ductular cells with Hh ligand-enriched medium induced mesenchymal genes; neutralizing Hh ligands inhibited this.BA is characterized by excessive Hh pathway activity, which stimulates biliary EMT and may contribute to biliary dysmorphogenesis. Other cholestatic diseases show similar activation, suggesting that this is a common response to cholestatic injury in infancy.

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Role of viruses in biliary atresia: news from mice and men.

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Role of viruses in biliary atresia: news from mice and men.

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