Targeting chemosensory signaling in Aedes aegypti mosquitoes

针对埃及伊蚊的化学感应信号传导

• 批准号: 9176663
• 负责人: DAVID NIGEL JONES
• 金额: $ 49.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-10 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176663
• 关键词: Aedes; Affect; Affinity; Arbovirus Infections; Behavior; Binding; Biological Assay; Biology; Bite; Blood; Chemicals; Complex; Computer Simulation; Culicidae; Data; Dengue; Dengue Infection; Dengue Virus; Disease; Drosophila odorant binding protein; Drug resistance; Feeding behaviors; Future; Genes; Genetic; Global Warming; Goals; Habitats; Helping Behavior; Human; Insecticides; Lead; Ligand Binding; Ligands; Link; Malaria; Mediating; Methods; Mosquito Control; Mosquito-borne infectious disease; Mutation; NMR Spectroscopy; Odors; Olfactory Pathways; Organ; Perception; Play; Process; Property; Proteins; Public Health; Publishing; Role; Salivary Glands; Semiochemicals; Signal Transduction; Site; Skin; Stimulus; Structure; Sweat; Sweating; System; Testing; Time; Tissues; Virus Diseases; West Nile virus; X-Ray Crystallography; Zika Virus; base; behavioral response; chikungunya; combat; cost; disease transmission; feeding; in vitro testing; insight; knock-down; novel; novel strategies; odorant-binding protein; prevent; protein function; protein structure; receptor; response; screening; signal processing; small molecule; three dimensional structure; transmission process; vector; vector mosquito; viral transmission; virtual

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.

摘要 疟疾、登革热和西尼罗河病毒等疾病的传播发生在 蚊子从人类宿主身上吸血随着对药物1、2、杀虫剂和 驱蚊剂3，4，以及全球变暖的影响，导致这些蚊子的栖息地扩大，包括在 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散发的化学信息素驱动的。 因此，干扰对这些“气味剂”的正常反应代表了一种替代方法， 这些蚊子的疾病传播（在8中进行了审查）。 气味结合蛋白（odorant binding proteins，OBP）在蚊子嗅觉系统中起着重要的作用 化学感受器复合物的化学信息素，以引起行为反应。最近的研究 发现在Ae。埃及伊蚊的两个OBP，AaegOBP 10和AaegOBP 22，直接调节血液摄食 蚊子的行为6.此外，登革热病毒感染的蚊子导致表达增加， 这两个OBP表明病毒感染增加了与血液相关的化学感受性反应， 喂食随后，敲除这两个OPB基因导致约30-45%的数量减少， 蚊子叮咬的痕迹因此，我们假设靶向AaegOBPs 10和22的活动将破坏 正常的蚊子行为，并有助于控制登革热病毒的传播。埃及人。 我们的总体目标是发现新的分子，可以破坏OBP功能，从而蚊子 吸血行为在这个项目中，我们将（1）定义每个目标OBP的组织特异性贡献， 吸血和寻找宿主(2)确定同时瞄准OBP 10和22是否代表 更好的减少吸血的策略。(3)确定每个OBP的三维结构， 这些在与配体结合时如何变化，以便我们可以（4）进行高通量的计算机筛选， 发现高亲和力结合的先导化合物，从而最大限度地发挥破坏正常OBP的潜力 功能发现能够靶向OBP功能并破坏血液喂养行为的化合物， 对公共卫生有直接影响，因为它将开辟新的途径，以防止重大疾病的传播。 蚊子传播的疾病，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。