Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage.
Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage.
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DOI：
10.7554/elife.00481
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发表时间：
2013-04-30
期刊：
影响因子：
7.7
通讯作者：
Abraham SN
中科院分区：
文献类型：
--
作者：
St John AL;Rathore AP;Raghavan B;Ng ML;Abraham SN
Dengue Virus (DENV), a flavivirus spread by mosquito vectors, can cause vascular leakage and hemorrhaging. However, the processes that underlie increased vascular permeability and pathological plasma leakage during viral hemorrhagic fevers are largely unknown. Mast cells (MCs) are activated in vivo during DENV infection, and we show that this elevates systemic levels of their vasoactive products, including chymase, and promotes vascular leakage. Treatment of infected animals with MC-stabilizing drugs or a leukotriene receptor antagonist restores vascular integrity during experimental DENV infection. Validation of these findings using human clinical samples revealed a direct correlation between MC activation and DENV disease severity. In humans, the MC-specific product, chymase, is a predictive biomarker distinguishing dengue fever (DF) and dengue hemorrhagic fever (DHF). Additionally, our findings reveal MCs as potential therapeutic targets to prevent DENV-induced vasculopathy, suggesting MC-stabilizing drugs should be evaluated for their effectiveness in improving disease outcomes during viral hemorrhagic fevers. DOI: http://dx.doi.org/10.7554/eLife.00481.001 Dengue fever is an infectious tropical disease that is transmitted by mosquitoes carrying dengue virus. Almost half of the world’s population lives in dengue-plagued regions and it is estimated that between 50 and 100 million people are infected annually. However, there is no effective vaccine and researchers have only a limited understanding of the mechanisms behind the disease. While most infected individuals experience fever, headache, muscle and joint pain, and a skin rash, a small percentage go on to develop a life-threatening condition known as dengue hemorrhagic fever (DHF). This is marked by internal bleeding, and by the leakage of water and salts from blood vessels (vascular leakage). At present, it is difficult to tell which patients will develop this complication, making it hard to tailor treatment appropriately. Here, St John et al. reveal that the vascular leakage that occurs in DHF is triggered by mast cells, which line blood vessels and regulate their permeability through the release of molecules such as histamines and leukotrienes. They also found that mice deficient in mast cells did not show dengue-induced vascular leakage, and that wild-type animals treated with drugs that block the actions of proteins produced by these cells, showed less vascular leakage than controls. Moreover, levels of an enzyme called chymase, another mast cell product, are higher in human patients with DHF than in those with dengue fever. Since chymase release occurs early in infection, tests for the presence of this enzyme could be used to predict which patients are likely to develop DHF. The work of St John et al. suggests new lines of inquiry into the mechanisms that lead some individuals infected with dengue fever to develop DHF, and indicates that drugs that target mast cells could offer an effective treatment. DOI: http://dx.doi.org/10.7554/eLife.00481.002
