Research Article: Gene Expression Profiling during Early Acute Febrile Stage of Dengue Infection Can Predict the Disease Outcome

Date Published: November 19, 2009

Publisher: Public Library of Science

Author(s): Eduardo J. M. Nascimento, Ulisses Braga-Neto, Carlos E. Calzavara-Silva, Ana L. V. Gomes, Frederico G. C. Abath, Carlos A. A. Brito, Marli T. Cordeiro, Ana M. Silva, Cecilia Magalhães, Raoni Andrade, Laura H. V. G. Gil, Ernesto T. A. Marques, Lisa F. P. Ng.

Abstract: We report the detailed development of biomarkers to predict the clinical outcome under dengue infection. Transcriptional signatures from purified peripheral blood mononuclear cells were derived from whole-genome gene-expression microarray data, validated by quantitative PCR and tested in independent samples.

Partial Text: The dengue virus is a member of Flaviviridae family, genus flavivirus with four antigenically distinct serotypes (DENV-1 to DENV-4). Dengue virus infection is a global public health concern, with an estimated incidence of 50–100 million cases of dengue fever (DF), resulting in 500,000 clinical cases of life-threatening dengue hemorrhagic fever syndrome (DHF) and 24,000 deaths per year [1]. DHF is characterized by vasculopathy, which results in sudden plasma leakage that reduces the blood volume and may result in hypovolemic shock, known as dengue shock syndrome (DSS). There is no antiviral therapy to treat dengue infection, neither are there means to prevent the development of DHF.

A functional genomic study was performed in order to obtain insights about the early immune mechanisms associated with dengue severity and to identify biomarkers to predict the infection outcome. Initial analysis resulted in the selection of 1981 candidate genes to be statistically evaluated. The analysis of degree of similarity between the samples in a 2 and 3-dimensional spaces has indicated that the DHF group formed a very tight pattern, whereas the remaining groups were more dispersed in the plot. In the 3-dimensional MDS plot the non-dengue samples (green spheres) are grouped close together, with only one sample outlier. The DHF samples (red spheres) are all at the far right side, while the DF samples (blues spheres) are more spread apart. These observations suggest the presence of a specific pattern of gene regulation against a dengue virus infection when compared to non-specific febrile disease. Welch’s two-sample t-tests were used for comparisons among the diagnostic groups: Non-Dengue vs. Dengue (DF+DHF) samples; DF vs. DHF samples and so on (Supplement material S4) but we will focus the discussion on the comparison between DHF versus DF.



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