Identification and disruption of mosquito heme transporters

描述(申请人提供)：埃及伊蚊是登革热、黄热病和基孔肯雅热病毒的主要传播媒介，是研究传播虫媒病毒的其他蚊子的模式系统。对于蚊子来说，获取血粉本质上是一种高风险、高回报的活动--几乎没有无限的资源来为产卵提供燃料，再加上极高水平的铁，必须对铁进行解毒，以防止自由基的产生和 氧化损伤。相比之下，血液中的铁既是卵子生产和发育所必需的微量营养素，也是启动卵黄形成过程的关键信号分子。因此，通过一个高度结构化的铁进口、出口和储存系统，铁超载和铁缺乏之间存在着微妙的平衡。在这项提案中，我们的目标是利用高通量测序(AIM 1)和靶向基因编辑(AIM 2)技术相结合的方式，识别和干扰参与细胞吸收分子铁和血红素的蚊子运输蛋白。蚊铁输入蛋白的鉴定将为疫苗、药物或转基因策略提供独特的靶点，旨在破坏蚊子的媒介能力，因为存在于消化道管腔表面的关键进口商/出口商如果存在于血粉中，将暴露于潜在的化学抑制剂或中和抗体。

DESCRIPTION (provided by applicant): Aedes aegypti is the main vector of dengue, yellow fever and chikungunya viruses, and is a model system for studies of other mosquitoes that vector arboviruses. The acquisition of a bloodmeal is by nature a high-risk, high reward activity for the mosquito- virtually unlimited resources to fuel egg production, combined with extraordinarily high levels of iron which must be detoxified to prevent free-radical production and oxidative damage. In contrast, blood-derived iron is both an essential micronutrient for egg production and development as well as a critical signaling molecule to initiate the vitellogenic process. Thus, a fine balance exists between iron overload and iron deficiency, achieved through a highly structured system of iron import, export and storage. In this proposal, we aim to identify and disrupt mosquito transport proteins involved in the cellular uptake of both molecular iron and heme using a combination of high-throughput sequencing (aim 1) and targeted gene editing (aim 2) technologies. The identification of mosquito iron import proteins would provide unique targets for vaccine, drug, or transgenic strategies aimed at disrupting mosquito vectorial capacity, as critical importers/exporters present on the lumenal surface of the digestive tract would be exposed to potential chemical inhibitors or neutralizing antibodies if present in the bloodmeal.