Fungal metabolites block malaria transmission

真菌代谢物阻止疟疾传播

基本信息

批准号：
10200641
负责人：
Jun Li
金额：
$ 43.53万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200641
关键词：
Africa Anopheles Genus Antibodies Antimalarials Area Binding Biochemical Biological Assay Blood Candidate Disease Gene Cells Cessation of life Chemicals Chromatography Circular Dichroism Spectroscopy Clinical Code Communities Community Health Computer Analysis Crude Extracts Culicidae Data Development Disease Double-Stranded RNA Drug Targeting Drug resistance Effectiveness Enzyme-Linked Immunosorbent Assay Exhibits Gene Expression Genes Genome Genomic Segment Genomics Goals Immunofluorescence Immunologic Individual Infection Insecta Insecticide Resistance Kenya Knowledge Libraries Malaria Malaria Vaccines Maps Mass Spectrum Analysis Mediating Midgut Molecular Molecular Biology Molecular Target NMR Spectroscopy Names Natural Products Oocysts Parasites Parasitic infection Pathway interactions Peptide Hydrolases Plasmids Plasmodium Plasmodium falciparum Population Process Proteins Public Health Reagent Recombinants Reporting Resources Role SNP genotyping Sampling Statistical Data Interpretation Structure Work base computational pipelines drug development fighting gene discovery gene product immunogenicity insight malaria infection malaria mosquito malaria transmission novel novel strategies parasite invasion pathogen small molecule success transmission process vector vector competence vector mosquito

项目摘要

ABSTRACT Malaria remains one of the most deadly diseases in the world, killing nearly a million people each year. Malaria is hard to control because the immunogenicity of malaria pathogens is very poor, which has made it hard to generate anti-malaria vaccines. The fast spread of insecticide-resistance in mosquito populations and drug- resistance of Plasmodium parasites further serves to increase the rate of malaria transmission. Therefore, there is critical need for the development of novel approaches for malaria control. Since malaria transmission depends on Plasmodium infected mosquitoes, inhibiting parasite infection in mosquitoes represents a novel and practical way to break malaria transmission. At present, most transmission-blocking studies focus on parasite gametocytes in blood with limited success because gametocytes are strongly resistant to drugs. However, very few efforts have been taken to use compounds against mosquito proteins to block malaria transmission. We recently identified the FREP1 gene in wild An. gambiae from malaria endemic areas in Kenya through association studies. Molecular and biochemical analyses revealed that the FREP1 protein mediates the invasion of multiple species of Plasmodium parasites in mosquito midguts through direct interaction with parasites. Based on these findings, we have developed a new high throughput platform to screen a library of natural fungal extracts targeting FREP1, which enabled our team to identify a bioactive compound named P-orlandin that significantly inhibits P. falciparum infection in mosquitoes. Based on these preliminary studies, we hypothesize that small compounds interfere with malaria-mosquito interaction will inhibit malaria transmission. Since multi-pathways involve Plasmodium invasion in mosquitoes, the overarching goal of this application is developing a novel and effective approach for using multiple fungal natural products to block malaria transmission by targeting multiple mosquito proteins that mediate parasites invasion in mosquitoes. We will use our successful collaborative studies as a springboard for identifying additional targets that mediate parasite transmission, as well as small molecules that disrupt the process of malaria transmission. Not only will the compounds we find serve as potential leads for field applications, but they will also serve as essential chemical probes to dissect the molecular biology of the novel pathways we uncover. In this study, we will identify additional candidate genes through genomic-block assistant-associated studies and verify their functional relationship with P. falciparum infection in mosquitoes. The candidate gene products that promote Plasmodium infection in mosquitoes will be chosen as targets to screen for small molecule compounds that block malaria transmission. This work will provide bioactive compounds that are leads for development of drugs or spray reagents to block malaria transmission. In addition, this work provides the malaria communities with new mechanistic insight into Plasmodium transmission to mosquitoes at a molecular level.

抽象的疟疾仍然是世界上最致命的疾病之一，每年夺去近一百万人的生命。疟疾由于疟疾病原体的免疫原性很差，很难控制。生产抗疟疾疫苗。蚊子种群中杀虫剂抗药性的快速传播和药物疟原虫的耐药性进一步增加了疟疾的传播率。所以，迫切需要开发新的疟疾控制方法。自从疟疾传播以来依赖于疟原虫感染的蚊子，抑制蚊子体内的寄生虫感染代表了一种新的方法以及阻止疟疾传播的实用方法。目前，大多数传输阻断研究都集中在血液中的寄生虫配子细胞的成功有限，因为配子细胞对药物有很强的抵抗力。然而，使用抗蚊子蛋白的化合物来阻止疟疾的努力却很少传播。我们最近在野生 An. 中发现了 FREP1 基因。冈比亚来自疟疾流行区肯尼亚通过协会研究。分子和生化分析表明 FREP1 蛋白通过直接介导蚊子中肠中多种疟原虫寄生虫的入侵与寄生虫的相互作用。基于这些发现，我们开发了一个新的高通量平台筛选针对 FREP1 的天然真菌提取物库，这使我们的团队能够识别出具有生物活性的名为 P-orlandin 的化合物可显着抑制蚊子中的恶性疟原虫感染。基于这些初步研究中，我们假设小化合物会干扰疟疾与蚊子的相互作用抑制疟疾传播。由于多途径涉及蚊子体内的疟原虫入侵，因此该应用程序的目标是开发一种新颖有效的方法来使用多种真菌天然产品通过针对介导寄生虫入侵的多种蚊子蛋白来阻止疟疾传播蚊子。我们将利用我们成功的合作研究作为确定其他目标的跳板介导寄生虫传播的分子，以及破坏疟疾传播过程的小分子。我们发现的化合物不仅可以作为现场应用的潜在先导化合物，而且还可以作为必要的化学探针来剖析我们发现的新途径的分子生物学。在这项研究中，我们将通过基因组区块助理相关研究确定其他候选基因并验证它们与蚊子恶性疟原虫感染的功能关系。促进候选基因产物将选择蚊子的疟原虫感染作为筛选小分子化合物的目标阻止疟疾传播。这项工作将提供生物活性化合物，这些化合物是开发阻止疟疾传播的药物或喷雾试剂。此外，这项工作还为疟疾社区提供了在分子水平上对疟原虫传播给蚊子的机制有了新的认识。