Proteomics analysis of peripheral blood monocytes from patients in early dengue infection reveals potential markers of subsequent fluid leakage

Infections caused by dengue virus (DENV) cause significant morbidity and mortality worldwide. The majority of patients have a mild course of dengue fever (DF) disease, however a proportion of infected individuals develop much more severe dengue haemorrhagic fever (DHF) resulting in circulatory collapse and multiorgan failure due to increased vascular permeability. Early detection of individuals likely to develop severe disease could lead to improved outcomes for patients, and help use healthcare resources more efficiently. At present there are no reliable markers during the earlier stages of infection that indicate which patients will go on to develop DHF. Our study was aimed at identifying proteins that are differentially regulated early during disease in peripheral blood monocytes (PBMC) of patients who subsequently develop DHF. Such proteins may also point at cellular pathways implicated in developing vascular leakage. PBMC were isolated from patients with a confirmed dengue infection, lysed and subjected to tandem mass tag mass spectrometry. One hundred and sixty proteins were differentially expressed in DENV-infected samples compared to healthy controls. These were mainly involved in type I interferon signaling, cytokine response, phagocytosis, haemostasis and cell adhesion. PBMC from DHF patients differentially expressed 90 proteins compared to individuals with DF; these were involved in down-regulation of platelet activation and aggregation, cell adhesion and cytoskeleton arrangement pathways. Proteins involved in oxidative stress and p38 MAPK signaling were upregulated in DHF samples during early infection compared to DF samples. The proteins reported here that are differentially regulated in PBMC early during infection could potentially serve as biomarkers to identify patients at risk of developing DHF at an early disease stage. This study also provides important observations on pathways implicated in severe DENV infection.