Temporal Dynamics of the Transcriptional Response to Dengue Virus Infection in Nicaraguan Children

Stephen J Popper,David A Relman,Angel Balmaseda,Eva Harris,Aubree Gordon,Minghsun Liu,Duane J Gubler

doi:10.1371/journal.pntd.0001966

Abstract

Dengue is the most prevalent mosquito-borne human illness worldwide. The ability to predict disease severity during the earliest days of the illness is a long-sought, but unachieved goal.We examined human genome-wide transcript abundance patterns in daily peripheral blood mononuclear cell (PBMC) samples from 41 children hospitalized with dengue virus (DENV) infection in Nicaragua, as well as 8 healthy control subjects. Nine patients had primary dengue fever (DF1), 11 had dengue fever with serologic evidence of prior DENV infection, i.e., secondary dengue fever (DF2), 12 had dengue hemorrhagic fever (DHF), and 9 had dengue shock syndrome (DSS). We identified 2,092 genes for which transcript abundance differed significantly between patients on days 3–6 of fever and healthy subjects (FDR<1%). Prior DENV infection explained the greatest amount of variation in gene expression among patients. The number of differentially expressed genes was greatest on fever day 3 in patients with DF1, while the number in patients with DF2 or DHF/DSS was greatest on day 5. Genes associated with the mitotic cell cycle and B cell differentiation were expressed at higher levels, and genes associated with signal transduction and cell adhesion were expressed at lower levels, in patients versus healthy controls. On fever day 3, a set of interferon-stimulated gene transcripts was less abundant in patients who subsequently developed DSS than in other patient groups (p<0.05, ranksum). Patients who later developed DSS also had higher levels of transcripts on day 3 associated with mitochondrial function (p<0.01, ranksum). These day 3 transcript abundance findings were not evident on subsequent fever days.In conclusion, we identified differences in the timing and magnitude of human gene transcript abundance changes in DENV patients that were associated with serologic evidence of prior infection and with disease severity. Some of these differential features may predict the outcome of DENV infection.

Highlights

As many as 100 million people are infected by dengue virus (DENV) each year, causing up to 40 million cases of dengue fever (DF)
We examined gene expression patterns in the blood of children hospitalized with DENV infection, and found that patients with differences in disease severity and history of previous DENV infection shared a common set of gene expression features, but the timing and magnitude of these features differed
A review of the clinical data associated with subjects in this study indicated that patients who developed dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) after hospitalization were more likely overall to have been hospitalized on fever day 4 than on any other day of illness

Summary

Introduction

As many as 100 million people are infected by dengue virus (DENV) each year, causing up to 40 million cases of dengue fever (DF). Identification and management of patients at risk for shock is difficult because the initial febrile phase of illness is similar in all patients, regardless of subsequent clinical severity, and because the onset of plasma leakage can lead to hypovolemic shock in less than 24 hours [2]. The severe disease in cases of secondary infection is thought to be due to enhanced entry of virus into Fcg receptor-bearing myeloid cells, mediated by nonneutralizing or sub-neutralizing anti-DENV antibodies, and/or aberrant activation of cross-reactive T-cells. Soluble factors and cell surface markers have been associated with severe disease, but in general, the cellular and molecular events that occur after the initial virus-host interactions and contribute to clinical outcome are not well understood (reviewed in [3])

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