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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林靜宜(Jing-Yi Lin) | |
| dc.contributor.author | Yen-Cheng Chen | en |
| dc.contributor.author | 陳彥丞 | zh_TW |
| dc.date.accessioned | 2022-11-25T05:34:12Z | - |
| dc.date.available | 2026-08-24 | |
| dc.date.copyright | 2021-10-01 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-26 | |
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Paul, A.V., et al., Identification of an RNA hairpin in poliovirus RNA that serves as the primary template in the in vitro uridylylation of VPg. J Virol, 2000. 74(22): p. 10359-70. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82020 | - |
| dc.description.abstract | 病毒A71型是會造成手足口症的其中一種病毒，是屬於小RNA病毒科、腸病毒屬的正股RNA病毒，一般的感染症狀為嘔吐、發燒、紅疹、起水泡等，少數情況下會在幼童引起嚴重的無菌性腦膜炎及腦炎等中樞神經感染症狀，嚴重甚至會導致死亡。然而腸病毒A71型如何在人體內擴散感染致中樞神經系統的作用機轉仍不清楚。為了探討腸病毒在各組織中的基因變異以及其組織特異性，利用實驗室過去所建立的帶有冷光報導基因的腸病毒A71型重組病毒以口餵感徑感染21天大人類SCARB2基因轉殖小鼠，可以觀測到病毒在動物模式中擴散以及複製的情況。本研究利用此動物模式連續偵測感染腸病毒小鼠之冷光訊號，並於第三天出現較強訊號時收取12個組織器官，萃取RNA並利用次世代定序偵測病毒基因的變異。資料分析後發現變異佔百分之二十五以上之單核酸變異包括脊髓中的5’UTR -G597C、VP1-V69和VP1-E213血液中的VP1-A188K和3B-K8N。接著我們進一步針對單核酸變異，利用點突變的方式製造突變病毒，並於細胞模式及動物模式分析該點突變在病毒組織特異性上所扮演的腳色。結果發現於中樞神經系統發現的5’UTR-G597C和3B-K8N單點突變病毒感染橫紋肌瘤細胞株細胞(Rhabdomyosarcoma cell)以及膠質母細胞瘤 (SF268 cell)下，產生之RNA複製能力、病毒蛋白質表現亮以及病毒效價與野生型相比略微下降。然而在動物實驗方面5’UTR-G597C及3B-K8N單點突變腸病毒以口餵感染小鼠模式動物可以發現，相比於野生病毒株有較早產生神經致病性的現象。利用次世代定序發現到了腸病毒在各個組織的基因變異，在小鼠動物實驗中證實這些變異點會增強腸病毒致病性，其可能是經由病毒擴散的機轉造成致病性的差異，而詳細機轉還有待更多的實驗來驗證。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T05:34:12Z (GMT). No. of bitstreams: 1 U0001-0208202113183100.pdf: 3484345 bytes, checksum: 0382613d59cf8482e55b6ccfa0c86ba4 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "口試委員審定書 i 致謝 ii 中文摘要 iii Abstract iv 1. Introduction 1 1.1. Enterovirus A71 1 1.1.1. The clinical symptoms of Enterovirus A71 1 1.1.2. The epidemiology of Enterovirus A71 2 1.1.3. Characterization of Enterovirus A71 genome 2 1.1.4. Life cycle of Enterovirus A71 4 1.2. EV-A71 virulence determinants 5 1.2.1. Genetically heterogenic composition of Enterovirus may regulate its infectivity 5 1.2.2. Recombination event between enteroviruses 7 1.3. Host innate immunity against EV-A71 infection 8 1.4. Animal models of EV-A71 infection 9 1.4.1. Non-human primate models 10 1.4.2. Mouse-adaptation models 10 1.4.3. Transgenic mouse models 11 1.5. Specific aim 12 2. Materials and Methods 14 2.1. Cells culture 14 2.2. Enterovirus propagation and concentration 14 2.3. Construction of single point mutation clone in EV-A71-MP4 15 2.3.1. Plasmid DNA extraction 15 2.3.2. Site directed mutagenesis PCR 16 2.3.3. Transformation 16 2.3.4. Linearization of EV-A71-MP4 infectious plasmid DNA 17 2.3.5. Gel extraction of linearized EV-A71-MP4 infectious plasmid DNA 17 2.3.6. In vitro transcription 18 2.3.7. RNA clean-up 19 2.3.8. Transfection 19 2.3.9. Purification of single plaque virus 20 2.4. Cell lines based analysis 21 2.4.1. Total RNA extraction from lysate of cell line 21 2.8. Mouse model analysis 24 2.8.1. 21-year-old hSCARB2-tg10 mouse was infected with EV-A71 by intra-gastric gavage (I.G.) 24 2.8.2. 21-year-old hSCARB2-tg10 mouse was infected with EV-A71 by intra-cerebral injection (I.C.) 25 2.8.3. Harvesting of organs and tissues from infected 21-year-old hSCARB2-tg10 mouse 25 2.8.4. In vivo imaging system 26 2.8.5. Total RNA extraction of mouse tissue 26 2.8.6. Reverse transcription and Quantification of EV-A71 viral load in tissues/organs 27 3. Results 29 3.1. The genetic diversity of EV-A71 was detected in infected hSCARB2 transgenic mouse 29 3.2. Single point variants detected in NGS data were cloned into EV-A71-MP4 infectious clone plasmid 30 3.3. Generation of EV-A71-MP4 5’UTR G597C and EV-A71-MP4 3B-K8N viruses 30 3.4. EV-A71-MP4 5’UTR G597C and EV-A71-MP4 3B-K8N have lower replication ability, translation ability and viral growth than EV-A71-MP4 in RD and SF268 cells 31 3.5. EV-A71-MP4 5’UTR G597C and EV-A71-MP4 3B-K8N created higher pathogenesis than EV-A 1-MP4 in intragastric-infected hSCARB2 tg10 mouse 33 3.9. Generation of EV-A71-Nluc-MP4 5’UTR G597C infectious clone plasmid 36 3.10. Generation of EV-A71-MP4-Nluc5 5’UTR G597C virus 37 4. Discussion 38 4.1. Summary 38 4.2. NGS in EV-A71 genome variants detection 38 4.3. The possible role of EV-A71-MP4 5’UTR in pathogenesis 40 4.4. The point mutation VP1-188T in EV-A71 may affect viral capsid generation 42 4.5. The possible role of single EV-A71 3B-K8N in pathogenesis 42 4.6. Conclusion 43 5. Tables 45 Table 1. The coverage and average depth of EV-A71-MP4-Nluc5 genome in the organs and tissues of EV-A71-MP4-Nluc5 infected hSCARB2-tg10 mouse. 45 Table 2. NGS depth and their nucleotide composition in genomic positions with minor variants 46 Table 3. Mortality rate of EV-A71-MP4 WT and variants intra-gastric inoculated 21-day-old hSCARB2 tg10 mouse 47 Table 4. Mortality rate of EV-A71-MP4 WT and variants intracerebral inoculated 21-day-old hSCARB2 tg10 mouse 48 Table 5. Primers 49 6. Figures 50 Figure 1. Quasispecies of EV-A71-MP4-Nluc5 in hSCARB2-tg10 mouse organs and tissues were analyzed with next-generation sequencing (NGS). 52 Figure 2. Generation of single nucleotide variants of EV-A71-MP4 infectious clone plasmid. 54 Figure 3. Generation of variant EV-A71-MP4 infectious clone plasmid. 56 Figure 4. EV-A71-MP4 5’UTR G597C and EV-A71-MP4 3B-K8N have lower replication ability, translation ability and viral growth than EV-A71-MP4 in RD and SF268 cells. 58 Figure 5. EV-A71-MP4 5’UTR G597C and EV-A71-MP4 3B-K8N created higher pathogenesis than EV-A71-MP4 in intragastric-infected hSCARB2 tg10 mouse. 60 Figure 6. EV-A71-MP4 5’UTR G597C and EV-A71-MP4 3B-K8N did not show pathogenesis differences between EV-A71-MP4 WT intracerebral route infected in hSCARB2 tg10 mouse. 62 Figure 7. EV-A71-MP4 5’UTR G597C can induce higher viral load in intragastric infected 21-day-old hSCARB2 transgenic mouse at 3 d.p.i. 63 Figure 8. Effects of EV-A71 5’UTR G597C on EV-A71 IRES activity in different neuron cell line. 64 Figure 9. Generation of single nucleotide variants of EV-A71-MP4-Nluc5 infectious clone plasmid. 66 Figure 10. Generation of single nucleotide variants of EV-A71-MP4-Nluc5 infectious clone. 68 7. Reference 69" | |
| dc.language.iso | en | |
| dc.subject | 次世代定序 | zh_TW |
| dc.subject | 腸病毒A71型 | zh_TW |
| dc.subject | 單一核苷酸變異 | zh_TW |
| dc.subject | 小鼠模式動物 | zh_TW |
| dc.subject | 活體冷光顯影系統 | zh_TW |
| dc.subject | mouse model | en |
| dc.subject | Enterovirus A71 (EV-A71) | en |
| dc.subject | in vivo imaging system (IVIS) | en |
| dc.subject | next-generation sequence (NGS) | en |
| dc.subject | single nucleotide variants (SNVs) | en |
| dc.title | 利用口餵途徑感染人類SCARB2基因轉殖小鼠探討腸病毒A71型變異點在致病性上的影響 | zh_TW |
| dc.title | Pathogenesis study of Enterovirus-A71 variants in intragastric infection of human SCARB2 -Transgenic weaned mice | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 施信如(Hsin-Tsai Liu),張淑媛(Chih-Yang Tseng),林郁里 | |
| dc.subject.keyword | 腸病毒A71型,活體冷光顯影系統,次世代定序,單一核苷酸變異,小鼠模式動物, | zh_TW |
| dc.subject.keyword | Enterovirus A71 (EV-A71),in vivo imaging system (IVIS),next-generation sequence (NGS),single nucleotide variants (SNVs),mouse model, | en |
| dc.relation.page | 74 | |
| dc.identifier.doi | 10.6342/NTU202101991 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-08-26 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| dc.date.embargo-lift | 2026-08-24 | - |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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