Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E.
Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E.
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DOI：
10.1371/journal.ppat.0030183
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发表时间：
2007-11
期刊：
影响因子：
6.7
通讯作者：
Diamond MS
中科院分区：
文献类型：
--
作者：
Avirutnan P;Zhang L;Punyadee N;Manuyakorn A;Puttikhunt C;Kasinrerk W;Malasit P;Atkinson JP;Diamond MS
登革病毒（DENV）非结构蛋白-1（NS 1）是一种分泌型糖蛋白，其不存在于病毒颗粒中，但在感染期间积累在细胞的上清液和质膜上。内皮细胞上细胞表面NS 1的免疫识别已被假设为在严重DENV感染期间发生的血管渗漏的机制。然而，目前还不清楚NS 1是如何与质膜结合的，因为它不包含跨膜序列基序。使用流式细胞仪和ELISA为基础的结合试验和缺乏选择性糖胺聚糖的突变细胞系，我们表明，可溶性NS 1结合回未感染细胞的表面主要通过与硫酸乙酰肝素和硫酸软骨素E的相互作用。登革病毒NS 1直接结合到许多类型的上皮细胞和间充质细胞的表面，但对大多数外周血细胞的附着很差。此外，与主动脉或脐带静脉内皮细胞相比，DENV NS 1优先结合培养的人微血管。这种结合特异性在原位得到证实，因为DENV NS 1与小鼠组织的肺和肝脏结合，但不与肠或脑内皮结合。组织内皮细胞对可溶性NS 1的差异结合以及随后抗NS 1抗体的识别可能导致在严重继发性DENV感染期间发生的选择性血管渗漏综合征。登革热病毒（DENV）是一种蚊子传播的病毒，感染人类，已成为全球新兴的传染病威胁。DENV存在四种血清型，最严重的病例与不同病毒血清型的继发感染有关。临床恶化的特征是出血和特定组织部位内皮的选择性血管渗漏。进一步了解DENV蛋白如何促成这种表型对于开发新型疫苗和识别有严重疾病风险的个体至关重要。登革病毒非结构蛋白1（NS 1）就是这样一种蛋白：在感染过程中，它被分泌并积累在上清液和细胞表面。在这项研究中，我们证明了可溶性DENV NS 1主要通过与特定的糖胺聚糖（硫酸乙酰肝素和硫酸软骨素E）相互作用附着于细胞亚群，包括一些但不是所有的内皮细胞。这在组织结合研究中得到证实，因为DENV NS 1结合肺和肝，但不结合肠或脑内皮。我们的研究结果表明，在严重的登革病毒感染中发生的选择性血管渗漏可能与不同组织中内皮细胞结合可溶性NS 1的相对能力有关，并且在继发感染期间被交叉反应性抗NS 1抗体靶向。
Dengue virus (DENV) nonstructural protein-1 (NS1) is a secreted glycoprotein that is absent from viral particles but accumulates in the supernatant and on the plasma membrane of cells during infection. Immune recognition of cell surface NS1 on endothelial cells has been hypothesized as a mechanism for the vascular leakage that occurs during severe DENV infection. However, it has remained unclear how NS1 becomes associated with the plasma membrane, as it contains no membrane-spanning sequence motif. Using flow cytometric and ELISA-based binding assays and mutant cell lines lacking selective glycosaminoglycans, we show that soluble NS1 binds back to the surface of uninfected cells primarily via interactions with heparan sulfate and chondroitin sulfate E. DENV NS1 binds directly to the surface of many types of epithelial and mesenchymal cells yet attaches poorly to most peripheral blood cells. Moreover, DENV NS1 preferentially binds to cultured human microvascular compared to aortic or umbilical cord vein endothelial cells. This binding specificity was confirmed in situ as DENV NS1 bound to lung and liver but not intestine or brain endothelium of mouse tissues. Differential binding of soluble NS1 by tissue endothelium and subsequent recognition by anti-NS1 antibodies could contribute to the selective vascular leakage syndrome that occurs during severe secondary DENV infection. Dengue virus (DENV) is a mosquito-transmitted virus that infects humans and has become a global emerging infectious disease threat. Four serotypes of DENV exist, and the most severe cases are associated with secondary infection with a different virus serotype. Clinical deterioration is characterized by bleeding and selective vascular leakage from endothelium in specific tissue sites. An increased understanding of how DENV proteins contribute to this phenotype is vital to developing novel vaccines and identifying individuals at risk for severe disease. DENV nonstructural protein-1 (NS1) is one such protein: during infection, it is secreted and accumulates in the supernatant and on the surface of cells. In this study, we demonstrate that soluble DENV NS1 attaches to subsets of cells, including some but not all endothelial cells, primarily via an interaction with specific glycosaminoglycans (heparan sulfate and chondroitin sulfate E). This was confirmed in tissue binding studies as DENV NS1 bound to lung and liver but not intestine or brain endothelium. Our findings suggest that the selective vascular leakage that occurs in severe DENV infection may be related to the relative ability of endothelial cells in different tissues to bind soluble NS1 and to be targeted by cross-reactive anti-NS1 antibodies during secondary infection.
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影响因子：
4.8
作者：
Broekelmann, TJ;Kozel, BA;Mecham, RP
通讯作者：
Mecham, RP
DOI：
10.1073/pnas.82.10.3197
发表时间：
1985-01-01
影响因子：
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影响因子：
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作者：
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