Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination
Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination
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DOI：
10.1126/scitranslmed.aaa3787
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发表时间：
2015-09-09
影响因子：
17.1
通讯作者：
Harris, Eva
中科院分区：
文献类型：
--
作者：
Beatty, P. Robert;Puerta-Guardo, Henry;Harris, Eva
四种登革热病毒血清型(DENV1至DENV4)是蚊媒黄病毒，每年在全球造成多达1亿例类似的登革热病例。严重的疾病被认为是由涉及血清型交叉反应抗体和T细胞的免疫病理过程引起的，这些抗体和T细胞共同诱导血管活性细胞因子，导致血管渗漏导致休克。然而，没有病毒蛋白直接参与触发内皮通透性，从而导致血管渗漏。DENV非结构蛋白1(NS1)在急性感染期间在患者的血液中分泌和循环；高水平的NS1与严重疾病有关。我们发现，单独接种DENV NS1小鼠会导致血管渗漏和关键炎症细胞因子的产生。此外，同时给予NS1和亚致死剂量的DENV2会导致致命的血管渗漏综合征。我们还证明了来自DENV1、DENV2、DENV3和DENV4的NS1可触发内皮屏障功能障碍，导致体外培养的人内皮细胞单层通透性增加。NS1免疫的多克隆小鼠血清或抗NS1的单抗可阻断体内和体外生理相关数量的NS1的这些致病作用，而从DENV1到DENV4的NS1免疫小鼠可抵抗DENV2的致死性攻击。这些发现为登革热血管泄漏的原因增加了一个以前被忽视的重要组成部分，确定了登革热治疗的新的潜在靶点，并支持将NS1纳入登革热疫苗。
The four dengue virus serotypes (DENV1 to DENV4) are mosquito-borne flaviviruses that cause up to similar to 100 million cases of dengue annually worldwide. Severe disease is thought to result from immunopathogenic processes involving serotype cross-reactive antibodies and T cells that together induce vasoactive cytokines, causing vascular leakage that leads to shock. However, no viral proteins have been directly implicated in triggering endothelial permeability, which results in vascular leakage. DENV nonstructural protein 1 (NS1) is secreted and circulates in patients' blood during acute infection; high levels of NS1 are associated with severe disease. We show that inoculation of mice with DENV NS1 alone induces both vascular leakage and production of key inflammatory cytokines. Furthermore, simultaneous administration of NS1 with a sublethal dose of DENV2 results in a lethal vascular leak syndrome. We also demonstrate that NS1 from DENV1, DENV2, DENV3, and DENV4 triggers endothelial barrier dysfunction, causing increased permeability of human endothelial cell monolayers in vitro. These pathogenic effects of physiologically relevant amounts of NS1 in vivo and in vitro were blocked by NS1-immune polyclonal mouse serum or monoclonal antibodies to NS1, and immunization of mice with NS1 from DENV1 to DENV4 protected against lethal DENV2 challenge. These findings add an important and previously overlooked component to the causes of dengue vascular leak, identify a new potential target for dengue therapeutics, and support inclusion of NS1 in dengue vaccines.