Vascular leakage in severe dengue virus infections: A potential role for the nonstructural viral protein NS1 and complement
Vascular leakage in severe dengue virus infections: A potential role for the nonstructural viral protein NS1 and complement
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DOI：
10.1086/500949
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发表时间：
2006-04-15
影响因子：
6.4
通讯作者：
Malasit, P
中科院分区：
文献类型：
--
作者：
Avirutnan, P;Punyadee, N;Malasit, P
背景血管渗漏和休克是登革出血热（DHF）和登革休克综合征（DSS）患者的主要死亡原因。30年前，补体激活被认为是一个关键的潜在事件，但补体激活的原因仍然未知。测试了主要的非结构性登革病毒（DV）蛋白NS 1以其膜结合和可溶形式激活人补体的能力。前瞻性分析了163例DV感染患者和19例其他发热性疾病患者的血浆样本的病毒载量以及NS 1和补体激活产物的水平。同时对9例DSS患者的血液和胸水进行了分析。可溶性NS 1激活补体完成，激活增强了多克隆和单克隆抗体对NS 1。在特异性抗体的存在下，补体也被细胞相关的NS 1激活。NS 1和终末SC 5 b-9复合物的血浆水平与疾病严重程度相关。DSS患者胸水中存在大量的NS 1、补体过敏毒素C5 a和补体末端复合物SC 5 b-9。由NS 1介导的补体激活导致局部和全身产生过敏毒素和SC 5 b-9，这可能有助于DHF/DSS患者发生血管渗漏的发病机制。
Background. Vascular leakage and shock are the major causes of death in patients with dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Thirty years ago, complement activation was proposed to be a key underlying event, but the cause of complement activation has remained unknown.Methods. The major nonstructural dengue virus ( DV) protein NS1 was tested for its capacity to activate human complement in its membrane-associated and soluble forms. Plasma samples from 163 patients with DV infection and from 19 patients with other febrile illnesses were prospectively analyzed for viral load and for levels of NS1 and complement-activation products. Blood and pleural fluids from 9 patients with DSS were also analyzed.Results. Soluble NS1 activated complement to completion, and activation was enhanced by polyclonal and monoclonal antibodies against NS1. Complement was also activated by cell-associated NS1 in the presence of specific antibodies. Plasma levels of NS1 and terminal SC5b-9 complexes correlated with disease severity. Large amounts of NS1, complement anaphylatoxin C5a, and the terminal complement complex SC5b-9 were present in pleural fluids from patients with DSS.Conclusions. Complement activation mediated by NS1 leads to local and systemic generation of anaphylatoxins and SC5b-9, which may contribute to the pathogenesis of the vascular leakage that occurs in patients with DHF/DSS.