Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/66372
標題: 牛乳鐵蛋白抗登革二型病毒感染之作用機制
Antiviral Activity of Bovine Lactoferrin Against Dengue Virus Type 2 Infection
作者: 陳若梅
Chen, Jo-Mei
關鍵字: dengue virus
登革病毒
bovine lactoferrin
牛乳鐵蛋白
出版社: 獸醫公共衛生學研究所
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摘要: 登革病毒(Dengue virus, DENV)主要是由節肢動物所傳播的病毒之一,以人為主要感染的對象。台灣自1942年首次爆發大規模感染登革病毒之後,1987年開始陸陸續續接傳出大小規模不等的流行。在感染登革病毒之後,病患只會對於感染的血清型具有免疫反應,因此可重複感染不同血清型的登革病毒。目前市面上並無有效的疫苗或治療的藥物,因此,登革病毒在公共衛生上所引發的議題仍有待解決。 乳鐵蛋白是一個會和鐵離子結合的醣蛋白,於腸道內負責鐵離子的運輸,存在於許多哺乳動物的體液中,其中尤其以乳汁中含量最多。乳鐵蛋白具有許多生物性功能,包括在腸道及血液中協助鐵的運輸促進鐵的吸收、具有抑制致病原的能力、免疫調節,被認為是哺乳動物免疫系統先天性防禦重要的成份之一。目前已知乳鐵蛋白可抑制多種病毒的感染,尤其是經由腸胃道及黏膜途徑感染的病毒,而本實驗室先前發現牛乳鐵蛋白亦可抑制蚊子傳播的日本腦炎病毒感染BHK細胞。因此,本實驗中將探討牛乳鐵蛋白對登革二型病毒之抗病毒效力。 實驗結果如下:(一)牛乳鐵蛋白可抑制登革二型病毒感染Vero細胞;(二)牛乳鐵蛋白對登革二型病毒的抑制作用主要是和細胞膜表面上分子及與病毒顆粒結合;(三)牛乳鐵蛋白抑制登革二型病毒感染的作用步驟主要是阻斷登革二型病毒的貼附及穿透的作用;(四)在牛乳 鐵蛋白抑制登革二型病毒感染Vero細胞中,heparan sulfate扮演重要的角色,因為只有在可正常表現heparan sulfate的CHO-K1細胞中可以看到牛乳鐵蛋白的 抑制效果;(五)除了heparan sulfate之外,加入重組LDLR可以中和牛乳鐵蛋白 抑制登革二型病毒感染Vero細胞,因此重組LDLR亦扮演重要角色;(六)於登革二型病毒感染Vero細胞過程中,加入anti-LDLR antibody及重組LDLR,可見登革病毒病毒斑的生成有減少的趨勢,顯示LDLR可能是登革二型病毒的受體之一;(七)經由IL-4、GM-CSF、TNF-α、ionomycin的刺激下,THP-1細胞成為可表現DC-specific ICAM-3 grabbing non-integrin(DC-SIGN)的成熟樹突細胞,在給予牛乳鐵蛋白的情況下可抑制登革病毒的感染率,因此DC-SIGN在牛乳鐵蛋白抑制登革二型病毒感染細胞作用中,亦扮演重要角色。 本研究證明,牛乳鐵蛋白可以藉由和細胞表面上heparan sulfate、LDLR及DC-SIGN結合,有效抑制登革病毒感染細胞。除此之外,首次發現LDLR可能是登革二型病毒的受體之一,但仍需進一步實驗證明之。
Dengue virus(DENV) is mainly disseminated by the arthropod and primarily infects humans. In Taiwan, the first dengue outbreak was in 1942, and frequently epidemic was since 1987. After infection, the neutralizing immune response prevents homologous, but not heterologous DENV infection. At present, dengue is an important public health problem, because there is no effective vaccine or treatment medicine. Lactoferrin exists in breast milk and mucous secretions; it is an iron-binding glycoprotein that functions on iron transportation in intestines. Lactoferrin have many biological functions, including transports iron in the intestines and blood, inhibits pathogen, modulates the immunity, and also involves in non-specific immune response. It has been shown that lactoferrin prevents several viral infections, especially intestines- and mucosa-transmitted viruses. Our previous study shown that bovine lactoferrin (bLF) prevents BHK cells infected with Japanese encephalitis virus (JEV). In this study, we evaluate the effect of bLF against DENV2 infection. Our results were summarized as below:(1) bLF prevents Vero cells infected with DENV2;(2) bLF inhibits DENV2 infection by interacting with the molecular(s) on the cellular membrane and with viral particle; (3) bLF blocks DENV2 entry into cells, including attachment, and endocytosis/penetration; (4) heparan sulfate plays a important role in the inhibitory effect of bLF against DENV2, because bLF inhibits DENV2 infection on HS-expressed CHO-K1 cells, but not on HS-deficient cells; (5) LDLR also plays a role in the inhibitory effect of bLF against DENV2, because rLDLR attenuates bLF against DENV2 infection; (6) LDLR was one of possible DENV2 receptors, because rLDLR and anti-LDLR antibody block DENV2 infection;(7) DC-SIGN also plays a role in the inhibitory effect of bLF against DENV2, because bLF inhibits DENV2 infection on DC-SIGN-expressed mature dendritic cells which derived from THP-1 cells after stimulated by adding recombinant IL-4, GM-CSF, TNF-α and ionomycin. In this study, we concluded that bLF inhibits DENV2 infection by interacting with membrane-bound heparan sulfate, LDLR, and DC-SIGN, and also with viral particle. In addition, our study also implicates for the first time that cell surface-expressed LDLR may be a possible receptor candidate for DENV2.
URI: http://hdl.handle.net/11455/66372
其他識別: U0005-2007200916431900
文章連結: http://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-2007200916431900
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