Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/93084
標題: Functional analysis of orf virus OV20.0 protein isoforms
比較分析羊傳染性化膿性病毒OV20.0蛋白異構體之功能
作者: 曾宇揚
Yeu-Yang Tseng
關鍵字: 羊傳染性化膿性病毒
OV20.0
orf virus
OV20.0 protein
PKR
dsRNA
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摘要: Orf virus (ORFV) infection causes pustule and ulceration around muzzle of small ruminants. Although it often occurs with low mobility and mortality, orf may be fatal in juvenile hosts. ORFV, belonging to genus parapoxvirus of the family Poxviridae, is an enveloped virus with double-stranded DNA genome. OV20.0 protein is produced from OV20.0L gene, an E3L ortholog, which is conserved in the genome of most members in Poxviridae. Vaccinia E3 (VV E3) has been studied extensively in these days; however sequences of VV E3 shares low identity with those of OV20.0. According to previous publication, OV20.0L could be translated into to two isoforms, full-length OV20.0 and N-terminal truncated one (sh20). Due to limited information of OV20.0 protein, our research focused on the translation mechanism of the isoform, comparative analysis of their cellular distribution and realizing their functions as well as their contribution to pathogenicity in mice model. First, we proved sh20 was translated from the third start codon of OV20.0L gene. In in vitro and in virus infection condition, both ORFV 20.0 and sh20 can hold the ability to bind double-stranded RNA (dsRNA), sequester the substrate of dsRNA-dependent protein kinase (PKR) that in turns inhibits the activity of downstream factor, eukaryotic initiation factor 2 (eIF2α), and influences cytokine releasing in different levels. Moreover, constructing recombinant virus and animal experiments clarify the role ORFV OV20.0 played in vivo. Although full-length OV20.0 and sh20 shared most functions in vitro, the ORFV recombinant virus which only expressed sh20, was attenuated in vivo. This data implied N-terminus of OV20.0 was required to induce intact pathogenicity in live animals.
羊傳染性化膿性病毒(Orf virus,ORFV)感染主要發生在反芻動物,造成其口腔潰瘍和膿皰等症狀,發生率和死亡率不高,然而對於年幼的宿主動物ORFV感染具有致死性。ORFV隸屬於痘病毒科的副痘病毒屬,具有封套,含雙股DNA的基因體。OV20.0 蛋白是由OV20.0L基因所轉譯,為E3的同源蛋白; E3基因高度保留於痘病毒科的許多成員,其中以牛痘病毒(vaccinia virus,VACV)的E3蛋白被研究最為透徹,但是牛痘病毒E3與羊傳染性化膿性病毒的OV20.0蛋白的胺基酸序列相似度低 (約為31%)。前人的研究顯示ORFV OV20.0L基因轉譯出全長及一分子量稍小的isoform (sh20蛋白),有鑒於現今對於ORFV OV20蛋白的功能所知有限,本研究試圖探討這兩個ORFV OV20.0異構體被轉譯的機制、比較兩者的功能、以及其對於病毒複製和致病力的影響。首先確認sh20蛋白為N-端缺陷的OV20.0異構體;是以第三個ATG當起始密碼所轉譯。在in vitro和病毒感染細胞中均可觀察到ORFV OV20.0和sh20蛋白皆具有結合雙股RNA (double-stranded RNA;dsRNA)的能力;dsRNA為dsRNA-dependent protein kinase (PKR)的受質,OV20.0與dsRNA結合推測可與PKR競爭其活化所需的受質。本研究進一步證實ORFV20.0的確抑制PKR的磷酸化,進而抑制PKR下游的訊息傳遞;例如,降低eukaryotic initiation factor 2 (eIF2α)的磷酸化、導致相關細胞素的合成與分泌受到不等程度的影響。雖然這兩個OV20.0異構體在in vitro以及細胞實驗系統中功能性極為相似,但是在小鼠攻毒試驗結果得知僅表現sh20的重組ORFV的致病性遠低於野外ORFV (具有全長OV20.0蛋白),由此推測 OV20.0異構體於生物體感染時可能扮演不同的角色,而N端為完整OV20.0功能所必須。
URI: http://hdl.handle.net/11455/93084
文章公開時間: 2017-05-06
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