Sequential Waves of Gene Expression in Patients with Clinically Defined Dengue Illnesses Reveal Subtle Disease Phases and Predict Disease Severity

Abstract

BackgroundDengue virus (DENV) infection can range in severity from mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Changes in host gene expression, temporally through the progression of DENV infection, especially during the early days, remains poorly characterized. Early diagnostic markers for DHF are also lacking.Methodology/Principal FindingsIn this study, we investigated host gene expression in a cohort of DENV-infected subjects clinically diagnosed as DF (n = 51) and DHF (n = 13) from Maracay, Venezuela. Blood specimens were collected daily from these subjects from enrollment to early defervescence and at one convalescent time-point. Using convalescent expression levels as baseline, two distinct groups of genes were identified: the “early” group, which included genes associated with innate immunity, type I interferon, cytokine-mediated signaling, chemotaxis, and complement activity peaked at day 0–1 and declined on day 3–4; the second “late” group, comprised of genes associated with cell cycle, emerged from day 4 and peaked at day 5–6. The up-regulation of innate immune response genes coincided with the down-regulation of genes associated with viral replication during day 0–3. Furthermore, DHF patients had lower expression of genes associated with antigen processing and presentation, MHC class II receptor, NK and T cell activities, compared to that of DF patients. These results suggested that the innate and adaptive immunity during the early days of the disease are vital in suppressing DENV replication and in affecting outcome of disease severity. Gene signatures of DHF were identified as early as day 1.Conclusions/SignificanceOur study reveals a broad and dynamic picture of host responses in DENV infected subjects. Host response to DENV infection can now be understood as two distinct phases with unique transcriptional markers. The DHF signatures identified during day 1–3 may have applications in developing early molecular diagnostics for DHF.

Monocyte-Plasmablast Crosstalk during Dengue

“…conducted parallel analyses to evaluate gene expression signatures in patients with high versus low viral load and in samples collected early versus late after symptom onset, and overall they observed similar patterns in samples with high viral load early in disease versus low viral load late in disease progression. These findings are consistent with previous studies, in which gene expression patterns exhibited temporal changes over the course of illness (Popper et al, 2012; Sun et al, 2013). Interestingly, when Kwissa et al .…”

Dengue Virus Infection Induces Expansion of a CD14+CD16+ Monocyte Population that Stimulates Plasmablast Differentiation

“…The blood transcriptome in dengue patients can be dependent on both the disease duration and VL (Popper et al, 2012; Sun et al, 2013). To determine molecular pathways associated with VL or disease duration, we first performed Pearson’s correlation analysis between all the 18,146 genes and the VL (Figure 2A) or days of symptomatic illness (Figure S1B) in the 28 acute dengue patients.…”

Assessment of immune status using blood transcriptomics and potential implications for global health

“…Indeed a significant number of studies pertaining to other infectious diseases that are not listed here have also been published, with for instance 11 articles to date on Dengue infection alone (e.g. [51][52][53]) or 5 on Staphylococcus aureus infection (e.g. [54,55]).…”