Severe dengue in children associates with dysregulation of lipid homeostasis, complement cascade and retinol transport

Abstract

DEAR EDITOR, Dengue is the most prevalent mosquito-borne flavivirus infection in humans with 3.9 billion people at risk of infection and 70% of the disease burden is in Asia.1,2 The four serologically and genetically distinct Dengue viruses (DENV1-4) can cause mild flu-like symptoms to lifethreatening disease involving vascular leakage and thrombocytopenia which can lead to shock and organ failure. Our study was designed to identify biomarkers of severe dengue by quantitative proteomics based on isobaric Tag for Relative and Absolute Quantitation (iTRAQ) labelling of plasma samples obtained from four different disease severity conditions: convalescent (CONV; n = 5), mild dengue/dengue illness (DI; n = 5), severe dengue without fluid leak (SD No FL; n = 5) and severe dengue with fluid leak (SD with FL; n = 5). The samples were divided into five sets for 4-plex iTRAQ labelling with each set consisting of all the four disease conditions (Figure S1 and Table S1). The distribution of peptide counts obtained across proteins that are differentially regulated in dengue infection is shown (Figure S2). Ninety-six proteins identified in DI, 101 in SD and 104 in SD with FL, respectively, are represented using Venn diagram to identify proteins unique to each of the three clinical symptoms (Figure 1A). We selected 54 proteins, which were identified in at least two out of the five iTRAQ runs (Dataset S1) and the expression levels of these proteins in dengue samples relative to convalescent samples were depicted in a heat map (Figure 1B). Network analysis was performed by Search Tool for the Retrieval of Interacting Genes/Proteins to predict interactions (both direct and indirect/functional) among the differentially expressed proteins (Figure 1C). A subset of identified proteins clustered into two prominent functional network namely the plasma lipid transport and complement pathways. Analysis for biological enrichment, molecular function and Kyoto encyclopaedia of Genes and Genomes pathway analysis also identified plasma lipoprotein regula-