Productive Dengue Virus Infection of Human Endothelial Cells Is Directed by Heparan Sulfate-Containing Proteoglycan Receptors
Productive Dengue Virus Infection of Human Endothelial Cells Is Directed by Heparan Sulfate-Containing Proteoglycan Receptors
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DOI：
10.1128/jvi.05008-11
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发表时间：
2011-09-01
影响因子：
5.4
通讯作者：
Mackow, Erich R.
中科院分区：
文献类型：
--
作者：
Dalrymple, Nadine;Mackow, Erich R.
登革热病毒导致血管内皮细胞渗漏，导致登革出血热和登革热休克综合征。血管系统的内皮细胞衬里调节毛细血管的通透性，并受到免疫和趋化因子反应的影响，从而影响内皮细胞的液体屏障功能。我们的发现表明，人内皮细胞对登革热病毒(4型)的感染非常敏感。我们发现，登革热病毒能够感染80%的原代人类内皮细胞，导致感染后1天迅速释放类似10(5)个病毒粒子。对登革病毒进入的潜在抑制物的分析表明，整合素和细胞受体的抗体和配体无法抑制登革病毒对内皮细胞的感染。相比之下，用肝素或硫酸肝素对细胞进行预处理可使感染登革热病毒的细胞减少60%至80%，用肝素酶III或蛋白水解酶对内皮细胞进行预处理可使登革热感染性降低80%。登革病毒与树脂固定的肝素特异性结合，过量的肝素竞争性地抑制结合，而不是其他配体。总而言之，这些发现表明登革热病毒特异性地附着在内皮细胞上含有硫酸肝素的蛋白多糖受体上。在与人类内皮细胞受体结合后，登革热病毒会引起一种高生产力的感染，有可能增加病毒传播和病毒血症。这为感染登革热病毒的内皮细胞提供了直接改变内皮屏障功能的可能性，有助于增强免疫细胞的活性，并作为免疫反应的潜在靶点，在登革热发病机制中发挥核心作用。
Dengue virus causes leakage of the vascular endothelium, resulting in dengue hemorrhagic fever and dengue shock syndrome. The endothelial cell lining of the vasculature regulates capillary permeability and is altered by immune and chemokine responses which affect fluid barrier functions of the endothelium. Our findings indicate that human endothelial cells are highly susceptible to infection by dengue virus (type 4). We found that dengue virus productively infects similar to 80% of primary human endothelial cells, resulting in the rapid release of similar to 10(5) virions 1 day postinfection. Analysis of potential inhibitors of dengue virus entry demonstrated that antibodies and ligands to integrins and cellular receptors were unable to inhibit dengue virus infection of endothelial cells. In contrast, pretreating cells with heparin or heparan sulfate resulted in a 60 to 80% reduction in dengue virus-infected cells, and pretreatment of endothelial cells with heparinase III or protease reduced dengue infectivity by >80%. Dengue virus bound specifically to resin immobilized heparin, and binding was competitively inhibited by excess heparin but not other ligands. Collectively, these findings suggest that dengue virus specifically attaches to heparan sulfate-containing proteoglycan receptors on endothelial cells. Following attachment to human endothelial cell receptors, dengue virus causes a highly productive infection that has the potential to increase viral dissemination and viremia. This provides the potential for dengue virus-infected endothelial cells to directly alter barrier functions of the endothelium, contribute to enhancement of immune cell activation, and serve as potential targets of immune responses which play a central role in dengue pathogenesis.