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Time course of gene expression profiling in the liver of experimental mice infected with Echinococcus multilocularis.

ABSTRACT: BACKGROUND: Alveolar echinococcosis (AE) is a severe chronic parasitic disease which behaves like a slow-growing liver cancer. Clinical observations suggest that the parasite, Echinococcus multilocularis (E. multilocularis) influences liver homeostasis and hepatic cell metabolism. However, this has never been analyzed during the time course of infection in the common model of secondary echinococcosis in experimental mice. METHODOLOGY/PRINCIPAL FINDINGS: Gene expression profiles were assessed using DNA microarray analysis, 1, 2, 3 and 6 months after injection of E. multilocularis metacestode in the liver of susceptible mice. Data were collected at different time points to monitor the dynamic behavior of gene expression. 557 differentially expressed genes were identified at one or more time points, including 351 up-regulated and 228 down-regulated genes. Time-course analysis indicated, at the initial stage of E. multilocularis infection (month 1-2), that most of up-regulated pathways were related to immune processes and cell trafficking such as chemokine-, mitogen-activated protein kinase (MAPK) signaling, and down-regulated pathways were related to xenobiotic metabolism; at the middle stage (month 3), MAPK signaling pathway was maintained and peroxisome proliferator-activated receptor (PPAR) signaling pathway emerged; at the late stage (month 6), most of up-regulated pathways were related to PPAR signaling pathway, complement and coagulation cascades, while down-regulated pathways were related to metabolism of xenobiotics by cytochrome P450. Quantitative RT-PCR analysis of a random selection of 19 genes confirmed the reliability of the microarray data. Immunohistochemistry analysis showed that proliferating cell nuclear antigen (PCNA) was increased in the liver of E. multilocularis infected mice from 2 months to 6 months. CONCLUSIONS: E. multilocularis metacestode definitely exerts a deep influence on liver homeostasis, by modifying a number of gene expression and metabolic pathways. It especially promotes hepatic cell proliferation, as evidenced by the increased PCNA constantly found in all the experimental time-points we studied and by an increased gene expression of key metabolic pathways.

SUBMITTER: Lin R

PROVIDER: S-EPMC3023716 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Time course of gene expression profiling in the liver of experimental mice infected with Echinococcus multilocularis.

Lin Renyong R Lü Guodong G Wang Junhua J Zhang Chuanshan C Xie Wenjuan W Lu Xiaomei X Mantion Georges G Martin Hélène H Richert Lysiane L Vuitton Dominique A DA Wen Hao H

PloS one 20110119 1

<h4>Background</h4>Alveolar echinococcosis (AE) is a severe chronic parasitic disease which behaves like a slow-growing liver cancer. Clinical observations suggest that the parasite, Echinococcus multilocularis (E. multilocularis) influences liver homeostasis and hepatic cell metabolism. However, this has never been analyzed during the time course of infection in the common model of secondary echinococcosis in experimental mice.<h4>Methodology/principal findings</h4>Gene expression profiles were ...[more]

PMID: 21283804

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Project description:For Samples GSM601017-28: The aim of this study was to use expression profiling to define transcriptional patterns and regulatory pathways that characterize the host liver response to E. multilocularis infection in the experimental model of secondary infection, to compare gene expression in this model to those described in the model of "primary infection", and to follow the changes in gene expression and in the expression of a cell proliferation marker over time during the complete chronic phase of E.multilocularis infection, following early and middle stages. For Samples GSM601029-40: The aim of this study was to use expression profiling to define transcriptional patterns and regulatory pathways that characterize the host liver response to E. multilocularis infection in the experimental model of secondary infection, to compare gene expression in this model to those described in the model of "primary infection", and to follow the changes in gene expression and in the expression of a cell proliferation marker over time during the complete chronic phase of E.multilocularis infection, following its middle and late stages. For Samples GSM601017-28: The anterior liver tissue sample of control mice group and alveolar echinococcosis mice group were obtained at each time point(1 month and 3 month). Biological replicates is 3. Then, total RNA from anterior liver of both groups were used as test sample, which labelled cy5 fluorescein, and the pool RNA of healthy BALB/c mice anterior liver was used as reference sample, which labelled cy3 fluorescein, and then hybridized to 32K Mouse Genome Array Genechips, representing about 25000 characterized murine genes. For Samples GSM601029-40: The anterior liver tissue sample of control mice group and alveolar echinococcosis mice group were obtained at each time point(2 month and 6 month). Biological replicates is 3. Then, total RNA from anterior liver of both groups were used as test sample, which labelled cy5 fluorescein, and the pool RNA of healthy BALB/c mice anterior liver was used as reference sample, which labelled cy3 fluorescein, and then hybridized to 36K Mouse Genome Array Genechips, representing about 25000 characterized murine genes.

Project description:BACKGROUND: Alveolar echinococcosis (AE) is a severe chronic hepatic parasitic disease currently emerging in central and eastern Europe. Untreated AE presents a high mortality (>90%) due to a severe hepatic destruction as a result of parasitic metacestode proliferation which behaves like a malignant tumor. Despite this severe course and outcome of disease, the genetic program that regulates the host response leading to organ damage as a consequence of hepatic alveolar echinococcosis is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We used a mouse model of AE to assess gene expression profiles in the liver after establishment of a chronic disease status as a result of a primary peroral infection with eggs of the fox tapeworm Echinococcus multilocularis. Among 38 genes differentially regulated (false discovery rate adjusted p</=0.05), 35 genes were assigned to the functional gene ontology group <immune response>, while 3 associated with the functional group <intermediary metabolism>. Upregulated genes associated with <immune response> could be clustered into functional subgroups including <macrophages>, <APCs>, <lymphocytes, chemokines and regulation>, <B-cells> and <eosinophils>. Two downregulated genes related to <lymphocytes, chemokines and regulation> and <intermediary metabolism>, respectively. The <immune response> genes either associated with an <immunosupression> or an <immunostimulation> pathway. From the overexpressed genes, 18 genes were subsequently processed with a Custom Array microfluidic card system in order to assess respective expression status at the mRNA level relative to 5 reference genes (Gapdh, Est1, Rlp3, Mdh-1, Rpl37) selected upon a constitutive and stable expression level. The results generated by the two independent tools used for the assessment of gene expression, i.e., microarray and microfluidic card system, exhibited a high level of congruency (Spearman correlation rho = 0.81, p = 7.87e-5) and thus validated the applied methods. CONCLUSIONS/SIGNIFICANCE: Based on this set of biomarkers, new diagnostic targets have been made available to predict disease status and progression. These biomarkers may also offer new targets for immuno-therapeutic intervention.

Project description:The neglected zoonotic disease alveolar echinococcosis (AE) is caused by the metacestode stage of the tapeworm parasite Echinococcus multilocularis. MicroRNAs (miRNAs) are small non-coding RNAs with a major role in regulating gene expression in key biological processes. We analyzed the expression profile of E. multilocularis miRNAs throughout metacestode development in vitro, determined the spatial expression of miR-71 in metacestodes cultured in vitro and predicted miRNA targets. Small cDNA libraries from different samples of E. multilocularis were sequenced. We confirmed the expression of 37 miRNAs in E. multilocularis being some of them absent in the host, such as miR-71. We found a few miRNAs highly expressed in all life cycle stages and conditions analyzed, whereas most miRNAs showed very low expression. The most expressed miRNAs were miR-71, miR-9, let-7, miR-10, miR-4989 and miR-1. The high expression of these miRNAs was conserved in other tapeworms, suggesting essential roles in development, survival, or host-parasite interaction. We found highly regulated miRNAs during the different transitions or cultured conditions analyzed, which might suggest a role in the regulation of developmental timing, host-parasite interaction, and/or in maintaining the unique developmental features of each developmental stage or condition. We determined that miR-71 is expressed in germinative cells and in other cell types of the germinal layer in E. multilocularis metacestodes cultured in vitro. MiRNA target prediction of the most highly expressed miRNAs and in silico functional analysis suggested conserved and essential roles for these miRNAs in parasite biology. We found relevant targets potentially involved in development, cell growth and death, lifespan regulation, transcription, signal transduction and cell motility. The evolutionary conservation and expression analyses of E. multilocularis miRNAs throughout metacestode development along with the in silico functional analyses of their predicted targets might help to identify selective therapeutic targets for treatment and control of AE.

Dataset Information

Time course of gene expression profiling in the liver of experimental mice infected with Echinococcus multilocularis.

Publications

Time course of gene expression profiling in the liver of experimental mice infected with Echinococcus multilocularis.

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