Targeting chemosensory signaling in Aedes aegypti mosquitoes

摘要 疟疾、登革热和西尼罗河病毒等疾病的传播发生在 蚊子从人类宿主那里摄取血餐。对药物1、2、杀虫剂和 驱蚊剂3、4和全球变暖的影响导致这些蚊子的栖息地扩大，包括 在美国，仍然需要开发新的方法来预防这些疾病的传播。 对于蚊子来说，吸血是由人类汗液和皮肤发出的信号化学物质驱动的。 因此，扰乱对这些“气味”的正常反应是防止 这些蚊子的疾病传播(第8章回顾)。 在蚊子嗅觉系统中，气味结合蛋白(OBP)在运输过程中起着核心作用 化学感受器复合体上的信号化学物质，以引起行为反应。最近的研究表明 在Ae.埃及人的两个OBP，AaegOBP10和AaegOBP22，直接调节血液摄取 这只蚊子的行为6.此外，登革热病毒感染蚊子导致其表达增加 这两个OBP表明病毒感染增加了与血液相关的化学感觉反应 喂食。随后，这两个OPB基因的敲除导致数量减少了约30%-45% 叮咬人的蚊子。因此，我们假设以AaegOBP 10和22为目标的活动将扰乱 蚊子行为正常，有助于控制登革热病毒的传播。埃及伊蚊。 我们的总体目标是发现可以破坏OBP功能的新分子，从而破坏蚊子 吸血行为。在这个项目中，我们将(1)定义每个目标OBP对组织的特定贡献 吸血和寻找寄主。(2)确定同时瞄准OBP10和22是否代表 减少供血的更好策略。(3)确定每个OBP的三维结构并 这些如何在与配体结合时发生变化，以便我们能够(4)在硅胶屏幕中实现高吞吐量以 发现高亲和力结合的先导化合物，从而最大限度地破坏正常的OBP 功能。能够靶向OBP功能和扰乱血液摄取行为的化合物的发现将 对公共卫生有直接影响，因为这将开辟新的途径来防止重大疾病的传播 蚊媒疾病，包括登革热病毒、疟疾、西尼罗河病毒和新出现的虫媒病毒感染 包括基孔肯雅热和寨卡病毒。

ABSTRACT The transmission of diseases including malaria, Dengue fever, and West Nile virus occurs when a mosquito takes a blood meal from a human host. With increased resistance to drugs 1, 2, insecticides and repellents 3, 4, and the effects of global warming leading to extended habitats for these mosquitoes, including in the USA, there is a continued need to develop new methods to prevent the transmission of these diseases. For mosquitoes, blood-feeding is driven by semiochemicals that emanate from human sweat and skin 7. Therefore, disrupting the normal responses to these “odorants” represents one alternative approach to prevent disease transmission by these mosquitoes (reviewed in 8). In the mosquito olfactory system, odorant binding proteins (OBPs) play a central role in transporting semiochemicals to the chemosensory receptor complex to elicit a behavioral response. Recent studies have discovered that in Ae. aegypti two OBPs, AaegOBP10 and AaegOBP22, directly regulate the blood-feeding behavior of this mosquito 6. Moreover Dengue virus infection of the mosquito led to an increased expression of these two OBPs suggesting that virus infection increases the chemosensory responses associated with blood feeding. Subsequently, knockdown of these two OPB genes resulted in a ~30-45% reduction in the numbers of mosquitoes that bite. Therefore, we hypothesize that targeting AaegOBPs 10 and 22 activities will disrupt normal mosquito behavior and help to control the transmission of Dengue virus by Ae. aegypti. Our overall goal is to discover novel molecules that can disrupt OBP function and thereby mosquito blood feeding behaviors. In this project we will (1) define the tissue specific contribution of each target OBP to blood feeding and host seeking. (2) Determine if targeting both OBP10 and 22 simultaneously represents a better strategy for reducing blood feeding. (3) Determine the three-dimensional structures of each OBP and how these change upon binding to ligands so that we can (4) perform high throughput in silico screens to discover lead compounds that bind with high affinity and so maximize the potential to disrupt normal OBP function. The discovery of compounds that can target OBP function and disrupt blood feeding behaviors would have a direct impact on public health as it would open up new avenues to prevent the transmission of major mosquito borne diseases including Dengue virus, malaria, West Nile virus and emerging arboviruses infections including chikungunya and Zika.