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Time since onset of disease and individual clinical markers associate with transcriptional changes in uncomplicated dengue.

van de Weg CA, van den Ham HJ, Bijl MA, Anfasa F, Zaaraoui-Boutahar F, Dewi BE, Nainggolan L, van IJcken WF, Osterhaus AD, Martina BE, van Gorp EC, Andeweg AC - PLoS Negl Trop Dis (2015)

Bottom Line: Sequential whole blood samples from DENV infected patients in Jakarta were profiled using affymetrix microarrays, which were analysed using principal component analysis, limma, gene set analysis, and weighted gene co-expression network analysis.Clinical diagnosis (according to the WHO classification) does not associate with differential gene expression.Overall, we see a shift in the transcriptome from immunity and inflammation to repair and recovery during the course of a DENV infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands.

ABSTRACT

Background: Dengue virus (DENV) infection causes viral haemorrhagic fever that is characterized by extensive activation of the immune system. The aim of this study is to investigate the kinetics of the transcriptome signature changes during the course of disease and the association of genes in these signatures with clinical parameters.

Methodology/principle findings: Sequential whole blood samples from DENV infected patients in Jakarta were profiled using affymetrix microarrays, which were analysed using principal component analysis, limma, gene set analysis, and weighted gene co-expression network analysis. We show that time since onset of disease, but not diagnosis, has a large impact on the blood transcriptome of patients with non-severe dengue. Clinical diagnosis (according to the WHO classification) does not associate with differential gene expression. Network analysis however, indicated that the clinical markers platelet count, fibrinogen, albumin, IV fluid distributed per day and liver enzymes SGOT and SGPT strongly correlate with gene modules that are enriched for genes involved in the immune response. Overall, we see a shift in the transcriptome from immunity and inflammation to repair and recovery during the course of a DENV infection.

Conclusions/significance: Time since onset of disease associates with the shift in transcriptome signatures from immunity and inflammation to cell cycle and repair mechanisms in patients with non-severe dengue. The strong association of time with blood transcriptome changes hampers both the discovery as well as the potential application of biomarkers in dengue. However, we identified gene expression modules that associate with key clinical parameters of dengue that reflect the systemic activity of disease during the course of infection. The expression level of these gene modules may support earlier detection of disease progression as well as clinical management of dengue.

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Related in: MedlinePlus

Gene set analysis of dengue signatures.The interferon pathway (left panel) is upregulated in the early stages of dengue, but not later. Segment plots indicate the significance of enrichment of particular Reactome gene sets and pathways. The longer the segment, the larger the enrichment. All segments longer than the grey segment are significant.
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pntd.0003522.g004: Gene set analysis of dengue signatures.The interferon pathway (left panel) is upregulated in the early stages of dengue, but not later. Segment plots indicate the significance of enrichment of particular Reactome gene sets and pathways. The longer the segment, the larger the enrichment. All segments longer than the grey segment are significant.

Mentions: The type I interferon pathway is known to be differentially expressed in DENV infection [19]. We investigated the interferon response during the course of infection by selecting genes from the interferon pathway (Reactome curated pathway database, 57 genes) and plotting their expression over time (Fig. 4). The expression of the majority of interferon genes was highly increased on the first day of admission, but decreased rapidly after that day and continued to be low, consistent with the notion that the interferon pathway is active in the early stages of dengue infection [4].


Time since onset of disease and individual clinical markers associate with transcriptional changes in uncomplicated dengue.

van de Weg CA, van den Ham HJ, Bijl MA, Anfasa F, Zaaraoui-Boutahar F, Dewi BE, Nainggolan L, van IJcken WF, Osterhaus AD, Martina BE, van Gorp EC, Andeweg AC - PLoS Negl Trop Dis (2015)

Gene set analysis of dengue signatures.The interferon pathway (left panel) is upregulated in the early stages of dengue, but not later. Segment plots indicate the significance of enrichment of particular Reactome gene sets and pathways. The longer the segment, the larger the enrichment. All segments longer than the grey segment are significant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358925&req=5

pntd.0003522.g004: Gene set analysis of dengue signatures.The interferon pathway (left panel) is upregulated in the early stages of dengue, but not later. Segment plots indicate the significance of enrichment of particular Reactome gene sets and pathways. The longer the segment, the larger the enrichment. All segments longer than the grey segment are significant.
Mentions: The type I interferon pathway is known to be differentially expressed in DENV infection [19]. We investigated the interferon response during the course of infection by selecting genes from the interferon pathway (Reactome curated pathway database, 57 genes) and plotting their expression over time (Fig. 4). The expression of the majority of interferon genes was highly increased on the first day of admission, but decreased rapidly after that day and continued to be low, consistent with the notion that the interferon pathway is active in the early stages of dengue infection [4].

Bottom Line: Sequential whole blood samples from DENV infected patients in Jakarta were profiled using affymetrix microarrays, which were analysed using principal component analysis, limma, gene set analysis, and weighted gene co-expression network analysis.Clinical diagnosis (according to the WHO classification) does not associate with differential gene expression.Overall, we see a shift in the transcriptome from immunity and inflammation to repair and recovery during the course of a DENV infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands.

ABSTRACT

Background: Dengue virus (DENV) infection causes viral haemorrhagic fever that is characterized by extensive activation of the immune system. The aim of this study is to investigate the kinetics of the transcriptome signature changes during the course of disease and the association of genes in these signatures with clinical parameters.

Methodology/principle findings: Sequential whole blood samples from DENV infected patients in Jakarta were profiled using affymetrix microarrays, which were analysed using principal component analysis, limma, gene set analysis, and weighted gene co-expression network analysis. We show that time since onset of disease, but not diagnosis, has a large impact on the blood transcriptome of patients with non-severe dengue. Clinical diagnosis (according to the WHO classification) does not associate with differential gene expression. Network analysis however, indicated that the clinical markers platelet count, fibrinogen, albumin, IV fluid distributed per day and liver enzymes SGOT and SGPT strongly correlate with gene modules that are enriched for genes involved in the immune response. Overall, we see a shift in the transcriptome from immunity and inflammation to repair and recovery during the course of a DENV infection.

Conclusions/significance: Time since onset of disease associates with the shift in transcriptome signatures from immunity and inflammation to cell cycle and repair mechanisms in patients with non-severe dengue. The strong association of time with blood transcriptome changes hampers both the discovery as well as the potential application of biomarkers in dengue. However, we identified gene expression modules that associate with key clinical parameters of dengue that reflect the systemic activity of disease during the course of infection. The expression level of these gene modules may support earlier detection of disease progression as well as clinical management of dengue.

Show MeSH
Related in: MedlinePlus