Abstract
BackgroundRecent in-vitro studies have suggested that mast cells are involved in Dengue virus infection. To clarify the role of mast cells in the development of clinical Dengue fever, we compared the plasma levels of several mast cell-derived mediators (vascular endothelial cell growth factor [VEGF], soluble VEGF receptors [sVEGFRs], tryptase, and chymase) and -related cytokines (IL-4, -9, and -17) between patients with differing severity of Dengue fever and healthy controls.Methodology/Principal FindingsThe study was performed at Children's Hospital No. 2, Ho Chi Minh City, and Vinh Long Province Hospital, Vietnam from 2002 to 2005. Study patients included 103 with Dengue fever (DF), Dengue hemorrhagic fever (DHF), and Dengue shock syndrome (DSS), as diagnosed by the World Health Organization criteria. There were 189 healthy subjects, and 19 febrile illness patients of the same Kinh ethnicity. The levels of mast cell-derived mediators and -related cytokines in plasma were measured by ELISA. VEGF and sVEGFR-1 levels were significantly increased in DHF and DSS compared with those of DF and controls, whereas sVEGFR-2 levels were significantly decreased in DHF and DSS. Significant increases in tryptase and chymase levels, which were accompanied by high IL-9 and -17 concentrations, were detected in DHF and DSS patients. By day 4 of admission, VEGF, sVEGFRs, and proteases levels had returned to similar levels as DF and controls. In-vitro VEGF production by mast cells was examined in KU812 and HMC-1 cells, and was found to be highest when the cells were inoculated with Dengue virus and human Dengue virus-immune serum in the presence of IL-9.ConclusionsAs mast cells are an important source of VEGF, tryptase, and chymase, our findings suggest that mast cell activation and mast cell-derived mediators participate in the development of DHF. The two proteases, particularly chymase, might serve as good predictive markers of Dengue disease severity.
Highlights
Dengue virus infection is associated with disease, ranging from Dengue fever (DF) to Dengue hemorrhagic fever (DHF) and/or Dengue shock syndrome (DSS)
As mast cells are an important source of vascular endothelial cell growth factor (VEGF), tryptase, and chymase, our findings suggest that mast cell activation and mast cell-derived mediators participate in the development of DHF
VEGF and soluble form of VEGF receptors (sVEGFR) levels in Dengue patients As mast cells are an important source of VEGF [46,47], we first measured VEGF levels in plasma samples from the DF (n = 19), DHF (n = 43), and DSS (n = 41) patient groups, and the control group, which consisted of febrile illness and healthy subjects
Summary
Dengue virus infection is associated with disease, ranging from Dengue fever (DF) to Dengue hemorrhagic fever (DHF) and/or Dengue shock syndrome (DSS). As severe diseases typically develop in individuals suffering secondary Dengue virus infection, host immunological factors appear to play a role in DHF and DSS [1]. DHF and DSS are characterized by increased vascular permeability and hemorrhagic manifestations [2], with the former phenotype recognized as the hallmark of these severe forms of Dengue. Recent studies on Dengue virus infection have demonstrated that the serum levels of vascular endothelial cell growth factor (VEGF)-A (formerly VEGF) are elevated in DHF patients [3]. To clarify the role of mast cells in the development of clinical Dengue fever, we compared the plasma levels of several mast cell-derived mediators (vascular endothelial cell growth factor [VEGF], soluble VEGF receptors [sVEGFRs], tryptase, and chymase) and related cytokines (IL-4, -9, and -17) between patients with differing severity of Dengue fever and healthy controls
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