Biogenic amines, malaria and manipulation of mosquito physiology and behavior.

项目总结/摘要 严重疟疾引起循环血液中生物胺、组胺和5-羟色胺水平的变化 （5-羟色胺，5-HT），并且这些变化与人类疾病病理学相关。组胺和 5-HT也是昆虫（包括蚊子）中重要的神经调质。我们的首要假设是 组胺和5-羟色胺，通过喂食蚊子而进入血液， 受体和改变内源性生物胺水平，生活史特征，行为和蚊子感染 成功扩大疟疾寄生虫传播。这些研究是创新的，因为它们将小说 从蚊子生物学到疟疾的临床观察，他们把重点放在蚊子对生物胺的摄入上， 血液中检测到的生理水平，它们将定义以前未探索的按蚊肠脑轴， 组胺能和多巴胺能信号传导。我们将通过三个具体目标来解决我们的总体假设。 在目标1中，我们将定义和模拟摄入组胺和5-HT的作用范围，单独和联合 在反映疟疾相关和健康血液水平的浓度下，对An.斯氏 恶性疟原虫和小鼠寄生虫约氏疟原虫约氏17 XNL感染成功。 我们还将研究这些治疗对服用第二次血餐的倾向的影响， 耐热性、繁殖力、窝卵数和寿命。在目标2中，我们将使用触角和视网膜记录， 行为生物测定，以确定摄入组胺和5-HT，单独和组合，对视觉的影响， 和嗅觉生理学。史蒂芬西在目标3中，我们将定量AN中的内源性组胺和5-HT。 Stephensi和MAP相关的组胺能和多巴胺能肠-脑信号传导网络。我们还将 摄入生物胺对内源性生物胺水平和使用影响的鉴定和建模 组胺和5-HT受体拮抗剂阻断疟原虫感染信号传导控制， 取第二份血粉在安体内繁殖史蒂芬西在完成这些研究后，我们会 与严重疟疾相关的生物胺浓度以及喂食蚊子摄入的生物胺浓度， 改变蚊子的生理学和生物学模式，预计有利于寄生虫传播。等 将来可以使用这些知识来将传输控制与临床干预（例如，减少 升高组胺和逆转5-HT的下降以减轻人类疟疾疾病）， 开发新型诱饵来操纵媒介蚊子中的生物胺信号传导。

Project Summary/Abstract Severe malaria induces changes in circulating blood levels of the biogenic amines histamine and serotonin (5-hydroxytryptamine, 5-HT) and these changes are associated with human disease pathology. Histamine and 5-HT are also important neuromodulators in insects, including mosquitoes. Our overarching hypothesis is that histamine and 5-HT, ingested in blood by feeding mosquitoes, signal through anopheline biogenic amine receptors and alter endogenous biogenic amine levels, life history traits, behavior and mosquito infection success to amplify malaria parasite transmission. These studies are innovative in that they connect novel mosquito biology to clinical observations in malaria, they focus on mosquito ingestion of biogenic amines at physiological levels detected in blood and they will define previously unexplored anopheline gut-brain axes for histaminergic and serotonergic signaling. We will address our overarching hypothesis with three Specific Aims. In Aim 1, we will define and model the scope of effects of ingested histamine and 5-HT, alone and in combination at concentrations that reflect malaria-associated and healthy blood levels, on An. stephensi infection success with Plasmodium falciparum and with the mouse parasite Plasmodium yoelii yoelii 17XNL. We will also examine the effects of these treatments on the tendency to take a second bloodmeal, thermotolerance, fecundity, clutch size and lifespan. In Aim 2, we will use antennal and retinal recordings and behavioral bioassays to define the effects of ingested histamine and 5-HT, alone and in combination, on visual and olfactory physiology in An. stephensi. In Aim 3, we will quantify endogenous histamine and 5-HT in An. stephensi and map associated histaminergic and serotonergic gut-to-brain signaling networks. We will also identify and model effects of ingested biogenic amines on levels of endogenous biogenic amines and use histamine and 5-HT receptor antagonists to interrupt signaling control of malaria parasite infection, tendency to take a second bloodmeal and reproduction in An. stephensi. With completion of these studies, we will establish that biogenic amine concentrations associated with severe malaria and ingested by feeding mosquitoes can alter mosquito physiology and biology in patterns that would be predicted to favor parasite transmission. Such knowledge can be used in the future to connect transmission control to clinical interventions (e.g., to reduce elevated histamine and reverse declines in 5-HT to mitigate human malarial disease) and for future development of novel lures to manipulate biogenic amine signaling in vector mosquitoes.