Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/66369
標題: 日本腦炎病毒低交叉反應類病毒顆粒引起之抗體反應分析
Characterization of the antibody response elicited by Japanese encephalitis virus cross-reactivity reduced virus-like particle
作者: 吳思嫺
Wu, Szu-Hsien
關鍵字: Japanese encephalitis virus;日本腦炎病毒;virus-like particle;類病毒顆粒
出版社: 獸醫公共衛生學研究所
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摘要: 
日本腻炎病毒 (Japanese encephalitis virus,JEV) 為黃病毒屬 (Flavivirus) 的一員,基因體上具有三個結構蛋白:核膜蛋白 (capsid,C) 、前趨膜蛋白 (membrane precursor,prM) 以及套膜蛋白 (envelope,E) 。其中套膜蛋白為引起宿主保護性免疫反應的主要抗原,在黃病毒屬病毒間相似度極高,因此易引起交叉反應抗體 (cross-reactive antibody) ,其會造成血清檢驗上偽陽性之發生,亦有可能造成「抗體依賴性免疫加強反應」( antibody dependent enhancement,ADE)。套膜蛋白分為三個 domain,融合胜肽 (fusion peptide, FP)位於domain II上 98-109 胺基酸位置,為高度保留區域;與病毒與細胞膜融合有關,具有免疫優勢 (immunodominant) 特性,但主要誘導出交叉反應抗體,且以不具中和能力的居多。先前本實驗室將日本腻炎病毒套膜蛋白fusion peptide區域G106、L107胺基酸位置分別以K、D取代,發現可以有效提高血清檢驗的特異度。因此本實驗即以此類病毒顆粒 (JEV-G106K/L107D,KD VLPs) 免疫 BALB/c小鼠,探討 fusion peptide 區域突變後,是否可以改變套膜蛋白引起之抗體反應特性。 本實驗重要結果,在老鼠免疫血清方面,日本腻炎病毒野生型 (wild-type,WT)及KD VLPs 引起抗體反應能力相似;但 WT VLPs引起之抗體有 64.5 % 辨認 fusion peptide 區域,而 KD VLPs 引起之抗體只有 29.2 % 作用在此區域,顯示 fusion peptide 區域的免疫優勢在突變後有降低趨勢。進一步取免疫之老鼠脾臟製備單株抗體,由 WT VLPs 免疫之老鼠中共篩選出 15 個單株抗體,10個 (66.7%) 為 Group cross-reactive MAbs、 5個 (33.3% ) 為 complex cross-reactive MAbs ,其中有 11 個作用在 fusion peptide 上;而由 KD VLPs 免疫之老鼠中共篩選出 12 個單株抗體,共有 1 個 (8.3%) 為 JEV type-specific MAbs , 3個 (25 %) Group-cross reactive MAbs 及 8 個 (66.7 % ) complex cross-reactive MAbs ,皆不作用在 fusion peptide ;中和能力分析方面,由 WT VLPs 免疫之老鼠中共篩選出的 15 個單株抗體,有 5 個 (33.3%) 具有中和能力,而 KD VLPs 免疫之老鼠中共篩選出的 12 個單株抗體,亦有 5 個 (41.7%) 具有中和能力。 KD VLPs 免疫之老鼠中篩選出的單株抗體中, 21-B7 單株抗體具JEV專一性,且具有高中和能力,進行抗原決定位分析後,發現其作用在日本腻炎病毒套膜蛋白 domain III上,尤其是胺基酸 S329、G332 及S389 ;進一步探討 21-B7 單株抗體中和病毒之機制,顯示其抑制病毒感染的 post-attachment 階段。 綜合以上,日本腻炎病毒低交叉反應類病毒顆粒 (KD VLPs) ,較不易誘導出作用在 fusion peptide 區域之抗體,而較可能誘導出 complex cross-reactive 抗體及高中和能力之日本腻炎病毒專一性抗體,因此利用此一抗原或許有可能部份降低或解決 ADE 所引起的問題,但仍需進一步探究。

Japanese encephalitis virus (JEV) is a member of the genus Flavivirus. The genome encodes three structural proteins, including capsid (C), premembrane/ membrane (prM/M, and envelope (E) proteins. The protective immune response primarily elicited by envelope protein. Because the high homology of envelope protein between flaviviruses, flavivirus infections elicit predominantly cross-reactive antibodies, that recognize fusion peptide. The cross-reactive antibodies confound the result of serodiagnosis and created antibody dependent enhancement (ADE) problem. The envelope protein has three domain (domain I, II and III). Fusion peptide (FP) (amino acid 98~109), involved in virus fusion, is a highly conserved loop at the end of domain II, and is immunodominant to elicit cross-reactive antibodies. Previously, our lab expressed FP-mutated (G106K-L107D) JEV virus-like particles (JEV KD VLPs) as cross-reactivity reduced antigen, and improved the specificity of serodiagnosis. Here, in order to study the property of mutated FP to elicit antibody, we characterize the antibodies elicited by JEV KD VLPs at serum and antibody-secreting cells levels.
Our important results were summarized as below. The immunogenicity of JEV wild-type (WT) and KD VLPs was similar. However, there were 64.5 and 29.2% antibodies against FP region elicited by WT and KD VLPs, respectively. Among the 15 monoclonal antibodies (MAbs) cloned from WT-immunized mouse spleen, 10 (66.7%) of them were group cross-reactive MAbs, 5 (33.3%) were complex cross-reactive MAbs, 11 MAbs recognize FP, and 5 MAbs had neutralizing activity. Among the 12 MAbs cloned from KD-immunized mouse spleen, 1of them was JEV type-specific MAbs, 3 (25%) were group-cross reactive MAbs, 3 (66.7 %) were complex cross-reactive MAbs, no MAbs
iii
recognize FP, and 5 (41.7%) MAbs had neutralizing activity. Especially, 21-B7 MAb, raised from KD-immunized mouse spleen, was JEV type-specific and has highly neutralizing activity. Epitope mapping found that the 21-B7 MAb recognize S329, G332 and S389 at domain III of JEV. The 21-B7 MAb neutralizes virus professionally at a post-attachment step of the viral life cycle. In this study, we concluded that that the JEV KD VLPs immunization elicits less antibodies against FP region, but toward to complex cross-reactive and highly neutralizing JEV type-specific antibodies. Thus, the JEV KD VLPs as immunogen might able to partially overcome the ADE problem, but need more further study.
URI: http://hdl.handle.net/11455/66369
其他識別: U0005-2007200914514100
Appears in Collections:微生物暨公共衛生學研究所

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