受到登革病毒 (DV) 感染的病人臨床症狀包含登革熱、登革出血熱、和登革休克症等，而血小板數低下、凝血機制異常或血管內皮細胞遭受到破壞，都可能是造成出血的原因。實驗室先前的研究指出，抗DV非結構蛋白1 (NS1) 抗體會和人類的內皮細胞及血小板產生交互作用，導致內皮細胞走向凋亡、血小板凝血機制異常，以及在小鼠主動免疫的實驗中發現，有延長小鼠出血時間的趨勢。利用蛋白質體學及序列比對分析的方式發現，NS1蛋白質C端的胺基酸與內皮細胞上標的蛋白質的序列非常相似。以安全性來考量疫苗的發展，我們將具有交互作用的抗原決定位進行切除，產生了含有DV NS1 N端胺基酸1-270與JEV NS1 C端胺基酸271-352的NS1嵌合蛋白，被命名為DJ NS1。實驗顯示DJ NS1抗體對人類內皮細胞及血小板的黏附能力較全長DV NS1抗體低，在小鼠模式中也發現，給予DV NS1主動免疫的小鼠有出血時間延長的趨勢，而DJ NS1主動免疫則不會造成相同的情形。另一方面，利用DV誘發小鼠出血的實驗模式，探討被動給予DJ NS1抗體是否可以提供保護能力，發現被動給予DJ NS1抗體可以減緩DV感染後造成出血時間延長的現象，以及降低在感染DV的局部皮膚上所造成出血的情形。KU812巨大細胞為DV的標的細胞之一，在缺乏抗體的促進作用之下，仍可以順利地被DV所感染。DJ NS1抗體可誘使被DV感染的KU812細胞走向細胞凋亡，同時，會抑制被DV感染的KU812細胞釋放MIP-1 alpha及MIP-1 beta 的能力。綜合以上的發現，DJ NS1可提供作為登革疫苗研發的新策略。

Patients infected by dengue viruses (DV) may display dengue fever, dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Hemorrhagic syndromes of DHF/DSS include thrombocytopenia, coagulopathy and vasculopathy, which are related with dysfunction of endothelial cells and platelets. Previous studies in our laboratory showed that antibodies (Abs) against DV nonstructural protein 1 (NS1) cross-react with human endothelial cells and induce apoptosis. Platelet dysfunction and bleeding tendency are also induced by anti-DV NS1 Abs. Using sequence homology analysis, we found that the C-terminal region of DV NS1 protein contains cross-reactive epitopes shared with self-antigens. For safety in vaccine development, the cross-reactive epitopes of DV NS1 protein should be deleted or modified. We have generated the chimeric NS1 protein, which consists of N-terminal DV NS1 (a.a. 1-270) and C-terminal JEV NS1 (a.a. 271-352) (designated DJ NS1). The anti-DJ NS1 Abs showed lower binding activity to human endothelial cells and platelets than that of anti-DV NS1 Abs. In the murine model, DV NS1 immunization caused prolonged bleeding time, but DJ NS1 immunization did not. Passive immunization with anti-DV NS1 or anti-DJ NS1 Abs could reduce DV-induced prolonged bleeding time and hemorrhage on the local skin. KU812 basophil/mast cell line was susceptible to DV infection without enhancing Abs. Anti-DJ NS1 Abs induced DV-infected KU812 cells to undergo apoptosis. Moreover, the expression of MIP-1 alpha and MIP-1 beta in DV-infected KU812 cells was also reduced by anti-DJ NS1 Abs. According to these findings, DJ NS1 may provide a strategy for dengue vaccine development.

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