Malaria transmission blocking through mosquito contact with treated surfaces

项目摘要 疟疾寄生虫是通过雌性按蚊的叮咬传播的。当前疟疾 控制战略广泛依赖于将抗疟疾药物用作人类疗法，以及 长效驱虫蚊帐和室内杀虫剂残留喷雾 美国国税局(IRS)以按蚊为目标。LLIN和IRS在预防疟疾方面发挥着关键作用， 占过去20年预防的所有病例的70%以上。然而，这些 大多数按蚊中出现了令人震惊的杀虫剂耐药性蔓延，这对干预措施造成了影响 撒哈拉以南非洲的人口，这威胁到他们的有效性。结合新技术的出现 关于疟原虫的抗药性，这些问题强调了需要新的工具来预防疟疾 变速箱。在最近的一项研究中，我们为一种新的疟疾控制战略奠定了基础，该战略基于 将抗疟疾药物与蚊子靶向干预相结合。我们的想法是将抗疟疾药物 在蚊帐或其他表面，如墙壁上，这样雌性按蚊就会降落在这些表面上 通过它们的腿吸收抗疟疾化合物，就像它们通常在LLIN或IRS上吸收杀虫剂一样。 作为原理的证明，我们在玻璃基质上涂上了有效的抗疟疾药物阿托瓦酮(ATQ)， 细胞色素b抑制剂，并允许冈比亚按蚊雌性在这个表面上休息几分钟 就在感染恶性疟原虫之前。值得注意的是，恶性疟原虫的发育完全是 在接触低浓度ATQ的女性中被废除(EC_(50)=1.77微克分子/平方米)。寄生虫 当蚊子在或之前24小时接触ATQ时，发育也完全中止 感染后12小时，当ATQ沉积在网状基质上时，显示出广泛的 这种方法的潜力。其他细胞色素b抑制剂也显示出类似的效果。在这个项目中，我们将 验证使用抗疟药在雌性按蚊体内杀死恶性疟原虫。具体来说，我们将：目标1) 筛选抗疟药文库，以确定在摄取时杀死恶性疟原虫的其他化合物 蚊子与疟疾药物加速器(MMV)合作 (Malda)和其他人；目标2)确定ATQ和我们屏幕上的Hit化合物杀死药物的能力- 抗药性恶性疟原虫，与马尔达和戴安·沃思合作在哈佛大学陈冯富珍 学校；以及目标3)评估蚊子中的杀虫剂抗性机制是否会影响 ATQ的摄取和疗效，与发展研究所(IRD， (布基纳法索)和利物浦热带医学院。通过将复合屏幕与 实验室和现场分析，我们的项目将验证具有抗疟疾活性的化合物在 蚊子媒介，帮助产生一种创新的疟疾控制工具。

PROJECT ABSTRACT Malaria parasites are transmitted by the bite of female Anopheles mosquitoes. Current malaria control strategies rely extensively on the use of antimalarial drugs as human therapeutics, and on long-lasting insecticide-treated bed nets (LLINs) and insecticide indoor residual sprays of house walls (IRS) to target the Anopheles mosquito. LLINs and IRS play a key role in malaria prevention, accounting for more than 70% of all cases prevented in the last two decades. However, these interventions suffer from the alarming spread of insecticide resistance emerging in most Anopheles populations in sub-Saharan Africa, which threatens their effectiveness. Combined with the emergence of drug resistance in Plasmodium parasites, these issues stress the need for new tools to prevent malaria transmission. In a recent study we have built the foundation for a novel malaria control strategy based on combining antimalarials with mosquito-targeting interventions. Our idea proposes to incorporate antimalarials on mosquito nets or other surfaces such as walls, so that female Anopheles landing on these surfaces will uptake the antimalarial compounds via their legs the way they generally uptake insecticides on LLINs or IRS. As a proof of principle, we coated a glass substrate with the potent antimalarial atovaquone (ATQ), a cytochrome b inhibitor, and allowed Anopheles gambiae females to rest on this surface for a few minutes immediately prior to P. falciparum infection. Strikingly, P. falciparum development was completely abrogated in females exposed to low concentrations of ATQ (EC50 = 1.77 µmol/m2). Parasite development was also completely aborted when mosquitoes were exposed to ATQ 24 hours prior to or 12 hours post infection, and when ATQ was deposited on a net substrate, demonstrating the broad potential of this approach. Other cytochrome b inhibitors showed similar effects. In this project, we will validate the use of antimalarials to kill P. falciparum in the Anopheles female. Specifically, we will: Aim 1) screen a library of antimalarials to identify additional compounds that kill P. falciparum upon uptake by the mosquito, in collaboration with Medicine for Malaria Venture (MMV), the Malaria Drug Accelerator (MalDA) and others; Aim 2) determine the ability of ATQ and hit compounds from our screens to kill drug- resistant P. falciparum parasites, in collaboration with MalDA and Dyann Wirth at the Harvard Chan School; and Aim 3) assess whether insecticide resistance mechanisms operating in the mosquito affect uptake and efficacy of ATQ, in collaboration with the Institut de Recherche pour le Développement (IRD, Burkina Faso) and the Liverpool School of Tropical Medicine. By combining compound screens with laboratory and field analyses, our project will validate the use of compounds with antimalarial activity in the mosquito vector, aiding in the generation of an innovative malaria control tool.