登革病毒(DV) 感染所造成的臨床症狀包括較輕微的登革熱乃至嚴重的登革出血熱和登革休克症，在病人身上可以觀察到血小板低下、凝血機制異常或血管內皮細胞遭受到破壞，都是造成出血的可能原因。實驗室先前研究證實，辨識DV非結構蛋白1 (NS1) 之抗體會與人類的內皮細胞及血小板產生交互作用，促使內皮細胞進行細胞凋亡並使血小板凝集機制異常。蛋白質體學及蛋白質序列分析比對的結果顯示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。考量以NS1為疫苗發展的安全性，我們將具有交互作用的抗原決定位去除，產生了含有DV NS1 N端胺基酸1-270與日本腦炎病毒(JEV) NS1 C端胺基酸271-352的NS1嵌合蛋白，並命名為DJ NS1。先前研究證實DJ NS1抗體對人類內皮細胞及血小板的結合能力較全長DV NS1抗體低，以DV NS1主動免疫的小鼠有出血時間延長的趨勢，但DJ NS1則不會造成類似的結果。在DV引起小鼠出血的模式中，發現被動給予DJ NS1抗體可以減緩DV感染所造成出血時間延長的現象，並降低DV感染在局部皮膚上造成的出血情形，證實抗DJ NS1抗體具保護小鼠對抗DV感染之效果。本實驗架構一主動免疫小鼠的模式，發現給予小鼠DJ NS1配合鋁鹽作為佐劑，四次接種後可引起小鼠體內高效價的抗體反應，使用高分子型奈米複合物作為佐劑時，三次接種即可引起小鼠體內明顯的抗體反應。為建立以stat-1基因剔除 (stat-1-/-)小鼠感染DV引起小鼠出血的模式，並進一步研究DJ NS1主動免疫對抗DV感染之保護性，我們先行測試stat-1-/-小鼠在DV引起小鼠出血的模式中所需的感染劑量。實驗證明使用9 ׬¬¬ 106 PFU/mouse的病毒，即可引起stat-1-/-小鼠出血，並造成小鼠出血時間的延長。細胞實驗的結果顯示，DV能夠感染表現DC-SIGN的THP-1人類單核球細胞以及HMEC-1人類內皮細胞。DV感染會促使表現DC-SIGN的THP-1細胞表現IL-8而給予抗DJ NS1抗體可抑制此現象，進一步發現抗DJ NS1抗體可引起被DV感染的HMEC-1細胞死亡。綜合以上結果，此研究證明抗DJ NS1抗體對於被DV感染的細胞提供了保護力，此外，本研究也提供了登革疫苗發展所需的重要資訊。

Dengue virus (DV) infection may cause dengue fever or severe dengue hemorrhagic fever and dengue shock syndrome, yet the pathogenic mechanisms remain unresolved. We previously found that antibodies (Abs) against DV nonstructural protein 1 (NS1) may cross-react with human endothelial cells and platelets, and cause their dysfunctions. Results of sequence homology analysis showed that the C-terminal region of DV NS1 protein contains cross-reactive epitopes sharing with self-antigens. For safety concern of vaccine development, the cross-reactive epitopes of DV NS1 protein should be deleted or modified. We have constructed a recombinant NS1 protein, in which the DV NS1 C-terminal a.a. 271 to 352 is replaced with JEV NS1 (designated DJ NS1). The anti-DJ NS1 Abs showed lower binding activity with human platelets and endothelial cells than that of anti-DV NS1 Abs. Active immunization with DV NS1 induced prolonged mouse tail bleeding time, but DJ NS1 immunization did not cause a similar effect. Passive immunization with anti-DJ NS1 Abs in DV-infected mice could reduce DV-induced prolonged bleeding time and hemorrhage on the local subcutaneous tissues. In the present study, we have established an active immunization model. Using alum as adjuvant, mice immunized with DJ NS1 proteins for four times could induce robust Abs response. While using polymer-based nanocomplex as adjuvant, three inoculations were sufficient to induce Abs response in mice. To verify the protective effects in DV-infected mouse model using stat-1 knockout (stat-1-/-) mice, we first examined the infection dose and found that 9 ׬¬¬ 106 PFU/mouse of DV could cause pathogenic effects in stat-1-/- mice. In vitro study suggested that both THP-1 monocytes and HMEC-1 endothelial cells were susceptible to DV infection. DV-infected DC-SIGN-transgenic THP-1 cells showed increased level of IL-8 production, which was reduced by anti-DJ NS1 Abs treatment. We also found that anti-DJ NS1 Abs could induce DV-infected HMEC-1 cell death. Taken together, this study shows the protective effect of anti-DJ NS1 Abs on DV-infected cells, and provides important information for strategies of vaccine development.

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