Abstract
BackgroundDengue 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 FindingsSequential 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/SignificanceTime 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.
Highlights
Dengue virus (DENV) infection is endemic in South-East Asia and has a large impact on society, both in terms of burden of disease as in economic costs [1]
An acute dengue virus infection usually starts with a febrile disease phase that can progress to severe disease around the time fever abates
Our results show that time after the onset of disease has a major impact on the transcriptome profile of patients with dengue, which is confirmed by comparing our results with three other dengue studies that included patients at different disease stages
Summary
Dengue virus (DENV) infection is endemic in South-East Asia and has a large impact on society, both in terms of burden of disease as in economic costs [1]. After 3–5 days, patients enter the critical phase of disease, characterized by resolution of fever. The majority of patients with non-severe dengue recover in this phase, but some patients develop severe symptoms, such as shock, haemorrhage, or organ impairment, and they are classified as having severe dengue. Typical for the development of severe disease in the critical phase of dengue is a rapid decrease in platelet count with a concomitant increase in haemo-concentration due to plasma leakage. The critical phase usually lasts 24–48 hours, after which patients enter the recovery phase. 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.
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