臺灣博碩士論文加值系統

病媒蚊的生活史需要藉由吸取脊椎動物的血以完成其卵巢的發育。目前已知有某些病媒蚊能傳播人類重要疾病的病原體。因而，了解如何調節病媒蚊生殖調控與病原體複製的機制，對於開發嶄新的蚊媒蚊控制策略是重要的。Wnt訊息傳遞和未折疊的蛋白反應（UPR）在果蠅的胚胎發育和細胞的逆境反應中扮演重要的角色。但是，我們對於這兩種途徑與病媒蚊中卵黃生成的交互作用了解甚少。此外，先前在哺乳類細胞的研究中也發現，登革病毒感染需要高血糖和蛋白質的轉錄後修飾（例如: SUMOylation），這些對哺乳動物中的病毒複製是重要的。然而，對於登革病毒的主要傳播媒介埃及斑蚊中，吸血時血液中葡萄糖濃度和病媒蚊體內蛋白質SUMOylation對登革熱病毒複製的影響知之甚少。在本論文中，我們證明了Wnt和TOR信號之間的交互作用與埃及斑蚊生殖調控有關。我們也發現，在埃及斑蚊中，母蚊吸血後可以藉由活化未折疊的蛋白反應來啟動細胞自噬，而這些反應對於病媒蚊的生殖調控也扮演了重要的角色。另外，我們也證實了血糖和蛋白質SUMOylation有利於病毒在埃及斑蚊體內複製。

Vertebrate blood is required for mosquito egg development. Some mosquito species are known to act as vectors for pathogens that cause devastating diseases in humans. Hence, understanding the mechanisms regulating egg developmental and pathogens replication are important basis for developing novel approaches to combat mosquito-borne diseases. The Wnt signaling pathway and the unfolded protein response (UPR) are key events in embryonic development and cellular stress response in model organisms, such as Drosophila. However, the interactions between these two pathways and vitellogenesis are poorly understood in the mosquito. Moreover, the blood glucose and post-translational protein modification such as SUMOylation have been shown to be required for dengue virus infection and important for viral replication in mammals. However, little is known about the effect of glucose levels and protein SUMOylation on dengue virus replication in the mosquito. Here, I demonstrated that there is a crosstalk between Wnt and TOR signaling, which are involved in the regulation of mosquito reproduction. I also showed that the autophagy-mediated egg production in the mosquito A. aegypti is regulated by UPR. In addition, I demonstrated that blood glucose and protein SUMOylation are beneficial to the virus replication and facilitates the virus transmission in the mosquito via the AKT and TOR signaling.

Table of Contents

Abstract 1
中文摘要 2
Chapter 1
General Introduction 9
Mosquito-borne diseases 10
Mosquito vitellogenesis 10
UPR and Autophagy 13
Dengue fever 16
The life cycle of the dengue virus in the mosquito vector 16
Blood glucose and dengue fever 17
SUMOylation 19
Chapter 2
Frizzled 2 is a key component in the regulation of TOR signaling mediated egg production in the mosquito Aedes aegypti 21
Abstract 22
Results 23
2.1. Cloning and characterization of A. aegypti Frizzled 2 23
2.2. Tissue-specific expression of AaFz2 26
2.3. Silencing AaFz2 significantly inhibited the fecundity of the female mosquito 27
2.4. Silencing AaFz2 inhibited the activation of TOR signaling 30
2.5. Silencing AaFz2 inhibited the Vg expression 32
Discussion 35
Chapter 3
The unfolded protein response is essential for reproduction control of the mosquito Aedes aegypti 38
Abstract 39
Results 40
3.1 Unfolded protein response (UPR) is activated after a blood meal in the fat body of mosquitoes 40
3.2 UPR is essential for mosquito fecundity 44
3.3 Both UPR and autophagy were activated after a blood meal in the mosquito 46
3.4 Amino acid treatment-activated UPR in the in vitro fat body culture system 50
3.5 UPR is the upstream regulator of autophagy in the control of Vg production 52
Discussion 55
Chapter 4
Effect of glucose on dengue virus replication in the mosquito Aedes aegypti 66
Abstract 67
Result 68
4.1 Glucose concentration is an important factor for dengue virus. 68
4.2 AKT signaling and TOR signaling are activated during the mosquito cell incubated at high glucose medium. 70
4.3 AKT and TOR signaling are involved in the glucose dependent enhancement of dengue virus replication and transmission in the mosquitoes. 71
Discussion 74
Chapter 5
Role of SUMOylation in dengue virus replication in the mosquito Aedes aegypti 78
Abstract 79
Result 80
5.1 Protein SUMOylation pathway is activated after a blood meal in the midgut of mosquitoes 80
5.2 protein SUMOylation pathway play an essential role on dengue virus replication in the mosquito. 82
5.3 Dengue virus envelope protein (E) and pre-membrane protein (prM) are potential target proteins of protein SUMOylation. 84
Chapter 6
General discussion 88
Signaling regulate the mosquito reproduction 89
Blood glucose and protein SUMOylation are beneficial to the virus replication and facilitates the virus transmission in the mosquito. 92
Material and methods 97
Rearing and maintenance 97
Blood feeding 97
RNA extraction 97
Reverse transcription (RT) 98
Polymerase chain reaction (PCR) 99
Quantitative polymerase chain reaction (Q-PCR) 99
Double-stranded RNA preparation-Plasmid construction 100
Double-stranded RNA synthesis 100
RNAi-mediated silencing and evaluation of silencing efficiency 101
Western blot analysis 102
Fat body culture 102
Treatment with UPR activator 103
Statistical analyses 103
References 104

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