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

PLoS Negl Trop Dis. 2015 Mar 13;9(3):e0003522. doi: 10.1371/journal.pntd.0003522. eCollection 2015 Mar.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aspartate Aminotransferases / blood
  • Biomarkers
  • Cohort Studies
  • Dengue / blood
  • Dengue / genetics*
  • Dengue / immunology
  • Female
  • Humans
  • Inflammation / genetics
  • Longitudinal Studies
  • Middle Aged
  • Platelet Count
  • Principal Component Analysis
  • Time Factors
  • Transcription, Genetic
  • Transcriptome*


  • Biomarkers
  • Aspartate Aminotransferases

Grant support

This study was supported by the Virgo Consortium, funded by the Dutch government project number FES0908, and by the Netherlands Genomics Initiative (NGI) project number 050-060-452. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.