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

项目摘要/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-羟色胺)，这些变化与人类疾病病理有关。组胺和 5-羟色胺也是包括蚊子在内的昆虫体内重要的神经调节剂。我们最重要的假设是 通过喂食蚊子在血液中摄取的组胺和5-羟色胺通过按蚊生物胺发出信号 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。这些研究具有创新性，因为它们将小说与 蚊子生物学对疟疾的临床观察，他们重点研究蚊子摄取生物胺的情况 在血液中检测到的生理水平，它们将定义以前未曾探索过的按蚊肠道-脑轴 组胺能和5-羟色胺能信号。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取组胺和5-羟色胺的影响范围，单独和 在一个反映疟疾相关和健康血液水平的浓度下进行组合。斯捷芬斯 用恶性疟原虫和小鼠寄生虫约氏疟原虫17XNL感染成功。 我们还将检查这些治疗对第二次进食血液的倾向的影响， 耐热性、繁殖力、卵子大小和寿命。在目标2中，我们将使用天线和视网膜记录和 行为生物测定以确定摄取的组胺和5-羟色胺单独和联合使用对视觉的影响 和嗅觉生理学。斯特芬西。在目标3中，我们将对AN的内源性组胺和5-羟色胺进行定量。 Stephensi和MAP相关的组胺能和5-羟色胺能肠脑信号网络。我们还将 识别和模拟摄入生物胺对内源性生物胺水平和用途的影响 组胺和5-羟色胺受体拮抗剂中断疟疾寄生虫感染的信号控制，倾向于 吃第二顿血，然后在一个月内繁殖。斯特芬西。随着这些研究的完成，我们将建立 与严重疟疾有关的生物胺浓度和喂食蚊子摄入的生物胺浓度可能 改变蚊子的生理和生物学，以预测有利于寄生虫传播的模式。是这样的 未来可以利用知识将传播控制与临床干预联系起来(例如，减少 组胺升高和5-羟色胺逆转下降以减轻人类疟疾疾病)和未来 开发新的诱饵来操纵媒介蚊子中的生物胺信号。

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.