Clinical Proteomics and Cytokine Profiling for Dengue Fever Disease Severity Biomarkers

Abstract

Dengue fever (DF) is a major global health burden with a pathophysiology that is still incompletely understood. Biomarkers that predict and explain susceptibility to DF and its progression to its more severe hemorrhagic form are much needed. DF is endemic in tropical and subtropical regions of the world, with a rapidly increasing incidence of disease severity. We conducted a clinical biomarker discovery study using both a case-control and longitudinal study design. Plasma proteome alterations in patients with DF (n = 12) and dengue hemorrhagic fever (DHF, n = 24) were analyzed in comparison to healthy controls (HCs, n = 16), using the isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomics methodology (false discovery rate of 1%, ≥2 peptides). Several proteins such as the alpha-2 macroglobulin, angiotensinogen, apolipoprotein B-100, serotransferrin, and ceruloplasmin were upregulated (fold change >1.2) in all DHF cases, and downregulated in DF (fold change <0.83), compared with HCs. Plasma cytokine profiling (8 DF, 8 DHF, and 8 HC) on two consecutive time points, at day 0 (day of admission) and days 5-7, found significant elevation in IL-1RA, IL-7, TNF-α, MCP1-MCAF, and MIP-1β levels, but only in the DHF cases, which is the severe disease, and not in DF, compared with HCs (p < 0.05). These new observations on changes in the plasma proteome and cytokine profiles in patients with dengue infection identify several putative molecular leads for future biomarker development and precision medicine in relation to forecasting DF disease severity.

Plectin is Required for Trans‐Endothelial Permeability: A Model of Plectin Dysfunction in Human Endothelial Cells After TNF‐α Treatment and Dengue Virus Infection

“…Those results also suggest that the high level of IP‐10, and low level of CXCL1 and platelets may play a role in the disruption of vascular endothelium resulting in vascular leakage after DENV infection. A recent study in plasma proteome using proteomics and cytokine profiling in dengue patients showed that an elevated level of IL‐1 RA, IL‐17, TNF‐α, MCP1‐MCAF, and MIP‐1β was observed only in the plasma of DHF patients . Previous studies of DENV2 infection on EA.hy926 cells reported transcellular transport to be affected rather than paracellular transport, whereas paracellular transport was observed to be profound in the cells treated with DENV2 and TNF‐α in the present study .…”

Clinical Proteomics Profiling for Biomarker Identification Among Patients Suffering With Indian Post Kala Azar Dermal Leishmaniasis

“…These proteins were found to play important role in disease pathology, for example α-1-acidglycoprotein is elevated during systemic tissue inflammation and is involved in neutrophil inactivation, chemotaxis, and oxidative metabolism (Pucadyil et al, 2004). The importance of plasma proteome profile for identification of disease specific protein biomarkers among various diseases were previously reported for Dengue patients (Jadhav et al, 2017), for Rheumatoid arthritis patients (Ohyama et al, 2012) and for VL patients (Bag et al, 2014). No such studies were reported previously for PKDL patients.…”

Differential Pattern of Soluble Immune Markers in Asymptomatic Dengue, West Nile and Zika Virus Infections

“…Inflammatory cytokines released mainly after T cell activation have been linked to the pathological events triggered by the infection 18,21,22 . SD has been associated with increased production of TNF-α, IFN-γ, IL-1ra, IL-4, IL-6, IL-10, CCL2, CCL3, CCL4, CXCL8 and CXCL10 22–29 . In our study, the A-DENV group also showed increased levels of these molecules, except for CXCL10.…”