Time since Onset of Disease and Individual Clinical Markers Associate with Transcriptional Changes in Uncomplicated Dengue


Background: Dengue virus (DENV) infection causes viral haemorrhagic fever that is characterized by ex- tensive 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 theWHOclassification) 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 im- munity 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 identi- fied gene expression modules that associate with key clinical parameters of dengue that re- flect the systemic activity of disease during the course of infection. The expression level of these genemodules may support earlier detection of disease progression as well as clinical management of dengue.

In PLoS Neglected Tropical Diseases