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

Abstract

Background

Dengue 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 Findings

In 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/Significance

Our 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.

Author Summary

The clinical outcome of DENV infection in humans can be DF or the more severe DHF and DSS. The individual's previous DENV exposure history, infecting serotypes, and host genetics are thought to be contributing factors to dengue disease severity. Our study contributed to the current dengue research field in the following ways: 1) Our study reveals the dynamics of host gene expression over each day post onset of symptoms. The gene transcription patterns enabled classification of dengue disease into 2 subtle phases: early acute and late acute. 2) The study identified gene markers differentiating severe dengue cases from non-severe cases with >90% accuracy. Taken together, our study offers insight into host responses in DENV-infected subjects and these results may be valuable for the future development of diagnostic tools for disease severity.