Deletion of the C-Terminal Region of Dengue Virus Nonstructural Protein 1 (NS1) Abolishes Anti-NS1-Mediated Platelet Dysfunction and Bleeding Tendency
Deletion of the C-Terminal Region of Dengue Virus Nonstructural Protein 1 (NS1) Abolishes Anti-NS1-Mediated Platelet Dysfunction and Bleeding Tendency
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DOI：
10.4049/jimmunol.0800672
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发表时间：
2009-08-01
影响因子：
4.4
通讯作者：
Lin, Yee-Shin
中科院分区：
文献类型：
--
作者：
Chen, Mei-Chun;Lin, Chiou-Feng;Lin, Yee-Shin
登革热出血性疾病的发病机制尚不完全清楚。我们之前已经证明，抗登革病毒(DV)非结构蛋白1(NS1)抗体与人血小板发生交叉反应，并抑制血小板聚集。根据序列同源性比对，交叉反应表位位于DV NS1的C-末端区域。在这项研究中，我们比较了单抗对全长DV NS1和缺失C-末端AA271-352(称为Delta C NS1)的NS1的影响。抗Delta C NS1单抗的血小板结合活性低于抗全长NS1单抗。抗全长NS1而不是抗Delta C NS1抗体抑制了血小板聚集，这被证明与整合素α(IIb)β(3)失活有关。我们发现，全长NS1高免小鼠的出血时间比正常对照小鼠长。相比之下，Delta C NS1超免疫小鼠的出血时间与正常对照组小鼠相似。被动应用抗DV NS1抗体，而不是抗Delta C NS1抗体，血清中抗体水平显著降低，这与抗体与血小板的结合有关。使用抗DV NS1抗体后，可观察到一过性的循环中的血小板丢失，但不能观察到抗Delta C NS1抗体的作用。综上所述，抗DV全长NS1抗体可引起血小板功能障碍和出血倾向，但抗Delta C NS1抗体不能引起血小板功能障碍和出血倾向。这些发现不仅对了解登革出血性疾病的发病机制有重要意义，而且对登革疫苗的研制也有重要意义。免疫学杂志，2009,183：1797-1803。
The mechanisms underlying dengue hemorrhagic disease are incompletely understood. We previously showed that anti-dengue virus (DV) nonstructural protein 1 (NS1) Abs cross-react with human platelets and inhibit platelet aggregation. Based on sequence homology alignment, the cross-reactive epitopes reside in the C-terminal region of DV NS1. In this study, we compared the effects of Abs against full-length DV NS1 and NS1 lacking the C-terminal aa 271 to 352 (designated Delta C NS1). Anti-Delta C NS1 Abs exhibited lower platelet binding activity than that of anti-full-length NS1. Anti-full-length NS1 but not anti-Delta C NS1 Abs inhibited platelet aggregation, which was shown to involve integrin alpha(IIb)beta(3) inactivation. We found that the bleeding time in full-length NS1-hyperimmunized mice was longer than that in the normal control mice. By contrast, Delta C NS1-hyperimmunized mice showed a bleeding time similar to that of normal control mice. Passively administered anti-DV NS1, but not anti-Delta C NS1, Ab level decreased markedly in serum and this decrease was correlated with Ab binding to platelets. A transient platelet loss in the circulation was observed after anti-DV NS1, but not anti-Delta C NS1, Ab administration. In summary, platelet dysfunction and bleeding tendency are induced by anti-full-length DV NS1 but not by anti-Delta C NS1 Abs. These findings may be important not only for understanding dengue hemorrhagic disease pathogenesis but also for dengue vaccine development. The Journal of Immunology, 2009, 183: 1797-1803.