建構Lambda red-CRISPR Cas9的桿狀病毒基因編輯系統-探討宿主決定因子及生產AAV顆粒之研究

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研究生：	張慧英 Indah Permata Sari
論文名稱：	建構Lambda red-CRISPR Cas9的桿狀病毒基因編輯系統-探討宿主決定因子及生產AAV顆粒之研究 Baculovirus Genome Editing Utilizing Lambda Red-Coupled CRISPR-Cas9 System – Host Range Extension Factor Determination and AAV Particle Production
指導教授：	彭明德 Perng, Ming-Der 吳宗遠 Wu, Tzong-Yuan
口試委員:	滕昭怡 Teng, Chao-Yi 陳怡寧 Chen, Yi-Ning 郭冠群 Kuo, Kwang-Chun
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2025
畢業學年度：	113
語文別：	英文
論文頁數：	124
中文關鍵詞：	桿狀病毒、宿主決定因子、基因編輯平台
外文關鍵詞：	host range determinant factor, CRISPR-Cas9, lambda red recombineering
相關次數：	點閱：43 下載：0
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摘要
桿狀病毒是一種主要感染昆蟲的雙股DNA病毒，廣泛應用於生物技術領域，例如外源蛋白質表現、基因傳遞及生物農藥。透過改造桿狀病毒基因體的方式能增加蛋白質表現、探討病毒基因的功能、以及增加病毒擴展宿主域的能力。本研究使用CRISPR-Cas9結合lambda red基因重組系統 (CCR9-lamda red)，能在無標記情況下，單一步驟就能精準的針對桿狀病毒基因體進行編輯。
我們利用CCR9-lamda red成功的在加州苜蓿葉蛾核多角體病毒(AcMNMPV) bacmid 中，剔除非必要基因p10 及 chiA/cath，驗證此基因編輯系統之可行性。在此p10 及 chiA/cath剔除的桿狀病毒基因體中，我們嘗試表現分泌型鹼性磷酸酶(SEAP)，發現SEAP在胞外的活性，以及在胞內的mRNA都有顯著增加，顯示此改造之病毒載體能有效增加分泌型蛋白的表現。此外，我們也利用CRISPR-Cas9結合的基因編輯系統，成功地將EGFP基因鑲嵌到病毒基因體中p10 及 chiA/cath的位點，驗證了此系統應用的多元性。
此外，我們也以CCR9-lamda red方法應用在探討桿狀病毒宿主決定因子。由加州苜蓿夜蛾核多角體病毒(AcMNPV)、家蠶核多角體病毒(BmNPV)以及豆莢螟核多角體(MaviMNPV)之基因體組成之桿狀病毒ABM病毒，能感染Sf21、BmN以及Mv532細胞株。在ABM基因體分析中，發現helicase以及一段從MaviMNPV基因體中來的pe38-lef2片段，為可能的宿主決定因子。研究中，我們將AcMNPV中的helicase 置換成ABM的helicase，此重組病毒能在BmN細胞中複製，確認了helicase為感染BmN細胞的決定因子。此外，進一步將pe38-lef2片段置換到AcMNPV中，重組病毒也能感染Mv532細胞，但若僅置換其中單一基因或是部分片段仍無法成功建立感染，顯示此片段中開放閱讀區的基因，對於跨越宿主域扮演協同角色。
最後，我們也利用基因編輯平台將AAV的基因鑲嵌入AcMNPV桿狀病毒不同的位點用以生產AAV病毒顆粒。透過生產出來的AAV，在感染HEK293細胞後能否成功表達EGFP蛋白作為驗證，我們發現無論是將AAV基因放在同一位點或是兩個位點，皆能成功的生產具功能性的AAV顆粒。
本研究驗證了CRISPR-Cas9-lambda red基因編輯系統，能作為另一個可以精準修改桿狀病毒基因體，來達到優化重組蛋白表現以及探討宿主決定因子的新穎技術。

關鍵字: 桿狀病毒、宿主決定因子、基因編輯平台

Abstract

Baculoviruses, insect-infecting double-stranded DNA viruses, have gained significant utility in biotechnology for protein expression, gene delivery, and agricultural biocontrol. Advances in genetic engineering have improved protein yields, provided insights into viral functions, and extended host range capabilities. This study highlights the application of the CRISPR-Cas9-coupled lambda red recombineering system for precise and efficient baculovirus genome editing, achieving single-step marker-less modifications.
As a proof of concept, we targeted non-essential genes (p10 and chiA/cath loci) in the Autographa californica multiple nucleopolyhedrovirus (AcMNPV) bacmid. The modified baculoviruses demonstrated elevated expression of functional secreted alkaline phosphatase (SEAP) expression and mRNA levels, validating the system’s efficiency for recombinant protein production. A knock-in of the egfp gene into these loci highlighted the versatility of CRISPR-Cas9-coupled system for introducing exogenous genes.
Further, we investigated host range determinants of the hybrid ABM baculovirus, derived from recombination of AcMNPV, Bombyx mori nucleopolyhedrovirus (BmNPV), and Maruca vitrata nucleopolyhedrovirus (MaviNPV). ABM’s infectivity extended to Sf21, BmN, and Mv532 cells. Genome analysis identified key open reading frames (ORFs) influencing host range, such as helicase and the flanking pe38-lef2 region. Replacing AcMNPV helicase with ABM helicase enabled replication in BmN cells, while Mv532 infectivity required the entire pe38-lef2 region. Neither individual nor partial combinations of ORFs extended the host range to Mv532 cells, suggesting the necessity of synergistic interactions among these ORFs.
Lastly, we integrated the adeno-associated virus’s (AAV) genes into an alternative locus of AcMNPV to produced functional AAV particles using the CRISPR-Cas9-coupled lambda red recombineering approach. A streamlined 1-locus and flexible 2-loci constructs facilitated efficient AAV particle production, validated by EGFP expression in HEK293 cells.
This study demonstrated the CRISPR-Cas9-coupled lambda red recombineering system as an alternative tool for precise baculovirus genome engineering, enhancing recombinant protein production and enabling investigations into host range determinants.

Keywords: Baculovirus, host range determinant factor, CRISPR-Cas9, lambda red recombineering, AAV

Acknowledgment......................................................I
Abstract..........................................................III
Content............................................................IV
Chapter 1 – Literature Review......................................2
A. Baculovirus Overview.............................................2
B. Baculovirus Infection Cycle......................................3
C. Baculovirus Classification.......................................4
D. Development of BEVS..............................................5
E. Lambda Red Recombineering........................................7
F. Clustered Regularly Interspaced Short Palindromic Repeats – CRISPR-Associated protein (CRISPR-Cas) Gene Editing.................9
G. Adeno-Associated Virus (AAV)....................................11
Chapter 2 – Baculovirus Genome Editing Utilizing CRISPR-Cas9-Coupled Lambda Red System..................................................14
Abstract...........................................................14
A. Introduction....................................................15
B. Experiment Rationale............................................18
C. Material and Method.............................................19
1. Cell lines......................................................19
2. Construction of sgRNA-expressing vector.........................19
3. Amplification and preparation of repair template................21
4. Construction of EGFP-fused secreted alkaline phosphatase protein (SEFP) transfer vector.............................................21
5. Preparation of electrocompetent cells...........................22
6. Generation of recombinant baculovirus through CRISPR-Cas9-coupled lambda red recombineering system...................................22
7. Determination of SEAP activity..................................23
8. Determination of relative mRNA levels...........................24
9. Determination of cell viability.................................24
D. Results and Discussion..........................................24
1. Generation of recombinant baculovirus bacmid with p10 locus deletion, chiA/cath loci deletion, and p10/chiA/cath loci simultaneous double deletion....................................................24
2. Comparison of SEAP activity of recombinant baculovirus with deleted p10 and chiA/cath loci.............................................27
3. Integration of the egfp gene into the p10 locus or chiA/cath loci mediated by the CRISPR-Cas9-coupled lambda red recombineering system.............................................................29
E. Conclusion......................................................29
Chapter 3 – Determination of Hybrid ABM Baculovirus’ Host Range Extension Factor...................................................40
Abstract...........................................................40
A. Introduction....................................................41
B. Experiment Rationale............................................43
C. Materials and Methods...........................................46
1. Cell Line.......................................................46
2. Construction of sgRNA-expressing vector.........................46
3. Construction of repair template.................................47
4. Generation of recombinant Ac-4e bacmid facilitated by the CRISPR-Cas9-coupled lambda red recombineering system......................48
5. Plasmid Curing..................................................48
6. Generation of recombinant baculovirus bacmid expressing secreted alkaline phosphatase (SEAP)........................................48
7. Generation of recombinant baculoviruses.........................49
8. Determination of SEAP activity..................................49
D. Results and Discussion..........................................50
1. The expression of ABM-derived helicase in the AcMNPV extended its host range to include BmN cells....................................50
2. Integration of the whole segment of ABM-derived pe38-lef2 loci into the homologous region of the AcMNPV genome extended the host range to Mv532 cells........................................................52
3. Integration of individual ABM-derived ORF from the ABM-pe38-lef2 loci into the homologous region of the AcMNPV genome failed to extend the host range to Mv532 cells......................................55
4. Integration of ABM-pe38 in combination with either ABM-hr1, ABM-ptp, and ABM-lef2 failed to extend the host range of AcMNPV to Mv532 cells..............................................................58
5. Comparison of the replication curve of Ac-4e, ABM-4e, Ac-4e-ABM-helicase, and Ac-4e-ABM-pe38-lef2-helicase.........................59
6. Comparison of protein expression levels in Ac-4e-, ABM-4e-, Ac-4e-ABM-helicase-, and Ac-4e-ABM-pe38-lef2-helicase-infected insect cells.    ...................................................................60
E. Conclusion......................................................62
Chapter 4 – Integration of AAV Genes into an Alternative Locus of Baculovirus Genome Using CRISPR-Cas9-Coupled Lambda Red Recombineering System.............................................................90
Abstract...........................................................90
A. Introduction....................................................91
B. Experiment Rationale............................................92
C. Materials and Methods...........................................94
1. Cell line.......................................................94
2. Plasmid construction............................................94
3. Generation of AcMNPV bacmid carrying AAV cap, rep, and egfp facilitated by CRISPR-Cas9-coupled lambda red recombineering.......95
4. Generation of recombinant baculovirus...........................96
5. Determination of recombinant AAV protein expression.............96
6. Production of AAV particle and infection of HEK293 cells........97
D. Results and Discussion..........................................97
E. Conclusion......................................................99
Chapter 5 – Conclusion and Future Study..........................108
A. Conclusion.....................................................108
B. Future Study...................................................109

                                

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