登革熱是最常見的由蚊子所傳播的病毒感染疾病，可引起多種疾病，包括自限性登革熱到登革熱重症。登革熱重症的主要特徵之一是血小板減少症和血管滲漏導致的出血性疾病。登革病毒（DENV）非結構蛋白1（NS1）是唯一能夠被登革病毒感染的細胞所分泌的非結構蛋白，近年來被認為在登革熱發病機制中扮演著關鍵角色。研究證實，登革病毒 NS1在登革病毒感染期間的血管滲漏中扮演著至關重要的作用，但關於登革病毒 NS1是否參與登革病毒所造成之血小板減少症的相關研究則是非常少。血小板不僅參與在調節凝血系統，最近的研究已經證實血小板在病毒感染（尤其是登革熱中）所導致之炎症中扮演著關鍵角色；與健康捐獻者的血小板相比，登革熱患者的血小板在其表面的P-選擇素（血小板活化標誌物）和磷脂酰絲氨酸（PS），皆會增加。此外，登革患者血清中的登革病毒非結構蛋白1含量與血小板數目呈現負相關；基於這些觀察，我們假設登革病毒非結構蛋白1可以誘導血小板活化和血管滲漏，從而導致出血性疾病。我們使用已建立之登革病毒誘導出血小鼠模型，發現非結構蛋白1確實參與在登革病毒誘導的皮下出血、出血時間延長和血小板減少症；直接注射登革病毒非結構蛋白1重組蛋白則能夠造成糖萼降解，血管滲漏和小鼠血小板計數減少等現象。這些結果表明登革病毒非結構蛋白1可以直接誘導血管滲漏和血小板減少，並引起出血性疾病。接下來，我們欲探討登革病毒非結構蛋白1是否可以直接引起血小板活化作用，並且進一步瞭解其潛在機制為何。首先，我們證明了登革病毒上清液能夠誘導人類洗滌血小板表面的P-選擇素的表達與PS暴露，而同樣為黃病毒科的茲卡病毒上清液則無法誘發此現象；並且當登革病毒上清液中的非結構蛋白1被去除後，由登革病毒上清液所造成之血小板活化與凋亡都受到抑制。另外，重組登革病毒非結構蛋白1蛋白所誘導之血小板活化與凋亡現象呈現劑量和時間依賴性。並且登革病毒非結構蛋白1也能夠在洗滌血小板系統和富含血小板的血漿中觸發血小板聚集。而登革病毒非結構蛋白1觸發的血小板活化增強了血小板與內皮細胞的粘附現象以及單核細胞和巨噬細胞的吞噬作用。而這些現象皆可被抗登革病毒非結構蛋白1抗體所抑制。接下來，我們研究了登革病毒 非結構蛋白1是否通過與Toll樣受體4（TLR4）結合而導致血小板活化。實驗結果顯示，抑制Toll樣受體4可顯著減少登革病毒非結構蛋白1所誘導的血小板活化和細胞凋亡，以及登革病毒在小鼠中所誘導的皮下出血，出血時間延長和體內血小板減少；然而，抑制TLR4只能部分降低登革病毒非結構蛋白1與血小板的結合以及登革病毒 非結構蛋白1誘導的血小板凝集。因此，我們推論登革病毒非結構蛋白1可能透過不同受體進而造成血小板活化。為了測試這種可能性，我們使用了洗滌過的血小板聚集系統，並且證明了登革病毒非結構蛋白1所誘導的血小板凝集現象可以被酪氨酸激酶（spleen tyrosine kinase，Syk）特異性抑製劑R406完全消除。此外，登革病毒非結構蛋白1誘導的血小板凝集依賴於次級介質，例如分泌性ADP和血栓烷，這樣的現象與膠原蛋白和C 型凝集素样受體2 （CLEC-2）刺激劑對血小板的激活作用相似。我們也進一步發現C 型凝集素样受體2拮抗劑能夠顯著抑制登革病毒非結構蛋白1誘導的血小板凝集反應，這樣的結果顯示登革病毒非結構蛋白1可通過C 型凝集素样受體2誘導血小板活化。最後，我們也進而評估了FDA批准的Src（原癌基因酪氨酸蛋白激酶）抑製劑dasatinib在登革感染的治療潛力。Dasatinib只能部分治療由登革病毒所引起的皮膚出血與出血延長現象，但可以有效挽救登革病毒所引起的血小板減少症。歸納以上重點，我們的結果證實了登革病毒非結構蛋白1不僅能通過Toll樣受體4造成血小板活化，還通過C 型凝集素样受體2和介導的Src家族激酶依賴性信號通路激活血小板。

Dengue, the most common mosquito-transmitted viral infection, can cause a range of diseases from self-limiting dengue fever to severe dengue. One of the major characters of severe dengue is bleeding disorder resulting from thrombocytopenia and vascular leakage. Dengue virus (DENV) nonstructural protein 1 (NS1), the only nonstructural protein that could be secreted by DENV-infected cells, has been considered as the last puzzle of the pathogenesis of dengue during the decade. Several studies have demonstrated that NS1 plays a crucial role in vascular leak during DENV infection. However, limited studies have been addressed whether DENV NS1 contributes to thrombocytopenia in dengue. Platelets, small anucleate cells present in the circulation, play a key role in regulating coagulation and hemostasis. Recent studies have identified platelets as major contributors to inflammation in viral infections, especially dengue. Compare to platelets from healthy donors, isolated platelets from dengue patients present increased P-selectin, a platelet activation marker, and exposed phosphatidylserine (PS) on their surface. Besides, a previous study has indicated that the circulation NS1 negatively correlates to platelet count in dengue patients. Based on these observations, we hypothesized that DENV NS1 could induce platelet activation and vascular leak thereby leading to the bleeding disorder. We used an established DENV-induced hemorrhagic mice model and found DENV NS1 plays a critical role in DENV-induced hemorrhage, bleeding time prolong, and thrombocytopenia. Indeed, direct injection of DENV NS1 recombinant protein could trigger glycocalyx degradation, vascular leak, and decrease of platelet count in mice. These results indicated that DENV NS1 could directly induce vascular leak and thrombocytopenia and then causes the bleeding disorder. Next, we investigated whether DENV NS1 could directly trigger platelet activation and if so, what is the underlying mechanism. At first, we demonstrated that DENV but not Zika virus supernatant could induce P-selectin expression and PS exposure in human washed platelets, both of which were abolished when NS1 was depleted from the DENV supernatant. In addition, recombinant DENV NS1, but not ZIKV NS1, could induce P-selectin expression and PS exposure in platelets in a dose- and time-dependent manner. Moreover, DENV NS1 could also trigger platelet aggregation in both washed platelet system and platelet-rich plasma. The activation of platelets triggered by DENV NS1 enhanced platelet adhesion to endothelial cells and phagocytosis by monocytes and macrophages. All of the effects induced by DENV NS1 could be blocked in the presence of anti-DENV NS1 F(ab’)2. Next, we investigated whether DENV NS1 activates platelets via binding to Toll-like receptor 4 (TLR4). Our results showed that TLR4 inhibition could significantly diminish DENV NS1-induced platelet activation in vitro as well as DENV-induced hemorrhage, bleeding time prolong and thrombocytopenia in vivo. However, the binding of DENV NS1 to platelets and DENV NS1-induced platelet aggregation could only be partially inhibited by TLR4 blocking. Therefore, it is possible that there is not only one receptor for DENV NS1 in platelets. To test this possibility, we used the washed platelet aggregation system. We demonstrated that DENV NS1-induced platelet activation is completely abolished by R406, a tyrosine kinase Syk (spleen tyrosine kinase, Syk) specific inhibitor. In addition, DENV NS1-induced platelet aggregation was dependent on secondary mediators such as secreted ADP and thromboxane A2, which is similar to platelet activation by collagen and CLEC-2 agonists. Furthermore, treatment of platelets with a CLEC-2 antagonist, AAWAP, could fully inhibit the DENV NS1-induced platelet aggregation indicating that DENV NS1 mediates platelet activation via CLEC-2. Finally, we tested the therapeutic potential of dasatinib, a FDA-approved Src (Proto-oncogene tyrosine-protein kinase) inhibitor. Dasatinib could only partially rescue DENV-induced skin hemorrhage and bleeding time prolong, but significantly rescued the DENV-induced thrombocytopenia. In conclusion, our results suggested that DENV NS1 activates platelets not only through TLR4 but a Src family kinase (SFK)-dependent signaling pathway mediated by CLEC-2 receptors.

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