Understanding mosquito commensal-to-pathobiont transition to develop new vector control tools

肠道微生物区系是控制蚊媒疾病的一种很有前途的工具，因为它有可能影响媒介能力。伊蚊肠道内的细菌共生体可以激活宿主的免疫反应，从而促进共生体和人类病原体如登革热、寨卡病毒和黄热病病毒的清除。最近的研究表明，肠道共生体可以分解尿苷并产生尿嘧啶，从而激活果蝇DUOX介导的免疫，从而选择性地消除病原菌，同时保留共生微生物。然而，这一过程是否发生在蚊子身上，是什么因素促使尿嘧啶的产生，以及它们对蚊子肠道中共生菌与人类病原体相互作用的影响仍未被探索。本论文研究了伊蚊微生物群与宿主DUOX免疫之间的相互作用以及伊蚊微生物群与ZIKV之间的相互作用。我检测了尿嘧啶对DUOX介导的免疫酶、活性氧(ROS)产生和蚊子适合性的影响，以评估尿嘧啶对这一途径的潜在选择性激活(第4章)。我还研究了细菌中的尿苷分解代谢途径以及触发它的条件，以阐明我们如何才能诱导共生体的发病，以便利用它们来控制媒介(第五章)。最后，我在实验室饲养和野外采集的埃及伊蚊中探索了ZIKV与蚊子微生物群的相互作用，以确定影响这些相互作用的因素(第6章)。这篇论文的发现揭示了蚊子免疫系统对尿嘧啶的性二态反应，并确定尿苷、血液和ZIKV是共生体致病的潜在触发因素。尿苷分解代谢似乎促进肠道定植并影响DUOX介导的免疫，尽管它对ZIKV感染的影响很小。此外，微生物组与ZIKV的相互作用受到宿主遗传背景和环境条件的影响，伊蚊肠道中的某些细菌分类群与ZIKV的耐受性有关。我希望这篇论文的见解将被用作设计媒介能力研究的基础，并为开发抗击媒介传播疾病的生物防治工具做出贡献。

The gut microbiota is a promising tool for controlling mosquito-borne diseases given its potential to influence vectorial capacity. Bacterial symbionts residing within the gut of Aedes mosquitoes can activate the host immune responses, thereby facilitating the clearance of both symbionts and human pathogens such as dengue, Zika (ZIKV), and yellow fever viruses. Recent investigations have revealed the activation of Drosophila DUOX-mediated immunity by gut symbionts that catabolise uridine and generate uracil, leading to the selective elimination of pathogenic bacteria while preserving commensal symbionts. However, whether this process occurs in mosquitoes, what factors instigate uracil production and their effect on the interactions between commensals and human pathogens in the mosquito gut remain unexplored. This thesis investigates the interactions between the Aedes microbiota and the host DUOX-mediated immunity alongside the interplay between the Aedes microbiota and ZIKV. I examined the impact of uracil on the enzymes of the DUOX mediated immunity, reactive oxygen species (ROS) production and mosquito fitness to evaluate the potential selective activation of this pathway by uracil (Chapter 4). I also studied the uridine catabolic pathway in bacteria and the conditions that can trigger it to elucidate how we can induce pathogenesis in symbionts in order to exploit them for vector control (Chapter 5). Finally, I explored the interactions between ZIKV and the mosquito microbiome in laboratory-reared and field-collected Aedes aegypti mosquitoes to identify the factors shaping these interactions (Chapter 6). The findings of this thesis revealed a sexually dimorphic response of the mosquito immune system to uracil and identified uridine, blood and ZIKV as potential triggers for pathogenesis in symbionts. Uridine catabolism appeared to facilitate gut colonisation and influenced DUOX-mediated immunity although it had minimal impact on ZIKV infection. Furthermore, microbiome-ZIKV interactions were found to be influenced by host genetic background and environmental conditions, with certain bacterial taxa in the Aedes gut correlating with refractoriness to ZIKV. I hope that the insights from this thesis will be used as a foundation for designing vector competence studies and contribute to the development of biological control tools to fight vector-borne diseases