Malaria transmission blocking through mosquito contact with treated surfaces

通过蚊子接触经过处理的表面来阻断疟疾传播

• 批准号: 10322993
• 负责人: Flaminia Catteruccia
• 金额: $ 74.44万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-04 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322993
• 关键词: Accounting; Affect; Africa South of the Sahara; Anopheles Genus; Anopheles gambiae; Antimalarials; Artemisinins; Beds; Biological Assay; Bite; Blood; Burkina Faso; Cessation of life; Collaborations; Combined Modality Therapy; Culicidae; Cytochrome a; Cytochromes b; Deposition; Development; Disease; Drug Kinetics; Drug resistance; Effectiveness; Exposure to; Feeds; Female; Foundations; Future; Generations; Genotype; Glass; Goals; Hour; Human; Infection; Insecticide Resistance; Insecticides; Intervention; Laboratories; Lead; Leg; Libraries; Malaria; Malaria prevention; Medicine; Methods; Modeling; Molecular Target; Multi-Drug Resistance; Parasite resistance; Parasites; Persons; Pharmaceutical Preparations; Phenotype; Plasmodium; Plasmodium falciparum; Play; Population; Prevalence; Reproduction; Residual state; Resistance; Rest; Schools; Stress; Surface; System; Testing; Therapeutic; Treatment Failure; Tropical Medicine; Validation; asexual; atovaquone; base; design; field study; fitness; inhibitor; innovation; lead candidate; malaria transmission; mutant; novel; prevent; resistance mechanism; resistant Plasmodium falciparum; screening; tool; transmission process; uptake; vector; vector mosquito

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.

项目摘要 疟疾寄生虫通过雌性按蚊的叮咬传播。当前疟疾 控制战略广泛依赖于使用抗疟药物作为人类治疗药物， 长效驱虫蚊帐和室内杀虫剂残留喷洒 墙（IRS），以针对按蚊。长效驱虫蚊帐和室内滞留喷雾杀虫剂在预防疟疾方面发挥着关键作用， 占过去二十年预防的所有病例的70%以上。但这些 大多数按蚊中出现的杀虫剂耐药性令人担忧地蔓延， 撒哈拉以南非洲的人口，这威胁到他们的有效性。结合出现的 疟原虫的抗药性，这些问题强调需要新的工具来预防疟疾 传输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， 将抗疟疾药物与针对蚊子的干预措施相结合。我们的想法是将抗疟药 在蚊帐或其他表面，如墙壁，使女性按蚊降落在这些表面将 它们通过腿吸收抗疟化合物，就像它们通常吸收长效驱虫蚊帐或IRS上的杀虫剂一样。 作为原理的证明，我们用有效的抗疟剂阿托伐醌（ATQ）涂在玻璃基底上， 细胞色素B抑制剂，并允许冈比亚按蚊雌性在此表面上休息几分钟 在恶性疟原虫感染之前。引人注目的是，恶性疟原虫的发育完全是 在暴露于低浓度ATQ的雌性中消除（EC 50 = 1.77 µmol/m2）。寄生虫 当蚊子在接种前24小时暴露于ATQ时， 感染后12小时，并且当ATQ沉积在网状基底上时，证实了广泛的 这种方法的潜力。其他细胞色素B抑制剂显示出类似的效果。在这个项目中，我们将 验证使用抗疟药杀死雌性按蚊体内的恶性疟原虫。具体而言，我们将：目标1） 筛选抗疟药物库，以鉴定在被恶性疟原虫摄取后杀死恶性疟原虫的其他化合物。 蚊子，与疟疾药物加速器疟疾药物创业公司（MMV）合作， （MalDA）和其他;目的2）确定ATQ和来自我们筛选的命中化合物杀死药物的能力- 抗恶性疟原虫，与MalDA和Dyann Wirth合作，在哈佛陈 目标3）评估蚊子的抗药性机制是否影响 ATQ的吸收和功效，与研究所合作， 布基纳法索）和利物浦热带医学院。通过将复合屏幕与 通过实验室和现场分析，我们的项目将验证具有抗疟活性的化合物在 蚊子病媒，帮助开发一种创新的疟疾控制工具。