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

肠道微生物群是控制蚊媒疾病的一个很有前途的工具，因为它有可能影响媒介的能力。居住在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，肠道共生体可以激活果蝇duox介导的免疫，这些共生体可以分解尿苷并产生尿嘧啶，从而在保留共生共生体的同时选择性地消除致病菌。然而，这一过程是否发生在蚊子身上，什么因素激发了尿嘧啶的产生，以及它们对蚊子肠道中共生体和人类病原体之间相互作用的影响，仍未得到研究。本文研究伊蚊微生物群与宿主duox介导的免疫之间的相互作用以及伊蚊微生物群与寨卡病毒之间的相互作用。我研究了尿嘧啶对DUOX介导的免疫、活性氧（ROS）产生和蚊子适应性的影响，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和触发它的条件，以阐明我们如何在共生体中诱导发病机制，以便利用它们进行媒介控制（第5章）。最后，我在实验室饲养和现场采集的埃及伊蚊中探索了ZIKV与蚊子微生物组之间的相互作用，以确定形成这些相互作用的因素（第6章）。本论文的研究结果揭示了蚊子免疫系统对尿嘧啶的两性二态反应，并确定尿嘧啶、血液和寨卡病毒是共生体发病的潜在触发因素。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，发现微生物组与寨卡病毒的相互作用受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寨卡病毒的耐受性相关。我希望本文的见解可以作为设计媒介能力研究的基础，并有助于开发生物控制工具来对抗媒介传播的疾病

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