Mechanisms of nutrient acquisition by malaria parasite mosquito stages

疟疾寄生虫蚊子阶段获取营养的机制

• 批准号: 9806568
• 负责人: Ashley M Vaughan
• 金额: $ 23.25万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806568
• 关键词: ATP-Binding Cassette Transporters; Address; Anopheles Genus; Antibodies; Artemisinins; Blood; CRISPR/Cas technology; Cells; Cessation of life; Chemistry; Choline; Combined Modality Therapy; Complex; Culicidae; Data; Defect; Development; Disease; Drug resistance; Environment; Epithelial Cells; Epithelium; Epitopes; Family; Family member; Female; Fertilization; Future; Gene Deletion; Germ Cells; Goals; Hemolymph; Human; Infection; Ingestion; Intervention; Invaded; Knock-out; Knowledge; Label; Laboratory mice; Lead; Life; Life Cycle Stages; Lipids; Lipoprotein (a); Lipoproteins; Malaria; Mammalian Cell; Methodology; Midgut; Modeling; Morbidity - disease rate; Nutrient; Oocysts; Parasites; Pharmacotherapy; Phenotype; Phospholipids; Plasmodium; Plasmodium falciparum; Plasmodium yoelii; Play; Process; Production; Research; Resources; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Salivary Glands; Side; Sporozoites; Time; Transcript; World Health Organization; cell motility; clinically relevant; comparative; experimental study; extracellular; human disease; insight; knockout gene; lipid metabolism; lipid transport; lipophilicity; lipophorin; malaria mosquito; male; mortality; novel; nutrition; pathogen; reverse genetics; transcriptome; transmission process; uptake; vector; vector mosquito; zygote

PROJECT SUMMARY AND ABSTRACT Plasmodium parasites cause the disease malaria. According to the World Health Organization there were 216 million cases of the disease worldwide which led to 445,000 deaths in 2016. The disease is thus formidable in its global burden and in an arena of malaria eradication and elimination, it is sobering to point out that between 2015 and 2016, deaths from the disease only fell by 1,000. Furthermore, the frontline drug treatment for uncomplicated malaria, artemisinin combination therapy, is beginning to fail due to the emergence of drug resistant malaria parasites and thus the great gains in malaria control achieved over the last decade could be wiped out in the near future. Novel interventions are thus still required. The malaria parasite has a complex life cycle, and in the case of the human disease, this relies on both a mosquito vector and a human host. The mosquito vector transmits infectious sporozoites to the human host which ultimately leads to a fulminant blood stage infection that causes all associated disease mortality and morbidity. During the blood stage of infection, sexual blood stage gametocytes can be acquired by the mosquito vector during blood meal acquisition where they mature into gametes. Gametes fuse to form a zygote and then a motile ookinete within the mosquito midgut. The ookinete traverses midgut epithelial cells before exiting through the basal side of the epithelium and develops as an extracellular oocyst, that is in contact with the hemocoel cavity and its associated nutrition-rich hemolymph. Life in an extracellular environment presents distinct challenges, and very little is known about how exactly the oocyst parasitizes its mosquito host in order to mature and release sporozoites, which migrate to the salivary glands and lay in wait for transmission to the next human host. Research has demonstrated that lipophorin, a lipoprotein complex derived from the mosquito bloodmeal can be taken up by developing oocysts, likely for the purpose of providing lipids for sporozoite production. However, whether this process is required for oocyst development is unclear. We have shown that an oocyst-expressed ATP binding cassette (ABC) transporter plays a role in the uptake of lipophorin and the deletion of the gene encoding this transporter leads to a severe defect in oocyst development, resulting in a significant decrease in oocyst maturation and time to sporozoite release. This proposal aims to fully elucidate the role of ABC transporters in oocyst maturation and their involvement in the acquisition of nutrients required for sporozoite production. We will use reverse genetics, spatial and temporal expression analyses, lipid labelling and heterologous expression to achieve these goals. An increased knowledge of this process could aid in the development of novel intervention to target malaria mosquito stages.

项目摘要和摘要 疟原虫引起疾病疟疾。根据那里的世界卫生组织 2016年，全球疾病的2.16亿例，导致445,000例死亡。 它的全球负担和消除疟疾和消除的舞台令人震惊，这令人震惊 在2015年至2016年之间，该疾病的死亡仅减少了1,000。此外，前线药物 由于疟疾，青蒿素联合疗法的治疗，由于 抗药性疟疾寄生虫的出现，因此在疟疾控制中获得了巨大的收益 在不久的将来可以消除过去十年。因此，仍然需要进行新颖的干预措施。 疟疾寄生虫具有复杂的生命周期，在人类疾病的情况下，这取决于 蚊子矢量和人类宿主。蚊子向量将感染性孢子虫传播到人类 宿主最终导致暴发性血液阶段感染，导致所有相关疾病死亡率 和发病率。在感染的血液阶段，可以通过 在获取血液粉期间，蚊子载体成熟到配子中。配子融合形成一个 合子，然后在蚊子中间的烟气中旋转。 Ookinete遍历中肠上皮细胞 在通过上皮的基底侧退出并以细胞外卵囊形成 与血液腔及其相关营养丰富的血淋巴接触。细胞外生活 环境提出了独特的挑战，对卵囊如何寄生的方式鲜为人知 蚊子宿主是为了成熟并释放孢子虫，迁移到唾液腺并躺在等待中 传输到下一个人类主机。 研究表明，源自蚊子的脂蛋白络合物是脂蛋白蛋白 血液可以通过开发卵囊来吸收血液，这可能是为了提供脂质的脂肪 生产。但是，尚不清楚卵囊发育是否需要此过程。我们已经显示了 表达卵囊的ATP结合盒（ABC）转运蛋白在摄取脂肪蛋白和 编码该转运蛋白的基因的缺失导致卵囊发育的严重缺陷，从而导致 在卵囊成熟和孢子岩释放的时间显着减少。该建议旨在完全 阐明ABC转运蛋白在卵囊成熟中的作用及其参与养分 Sporozoite生产所必需的。我们将使用反向遗传学，空间和时间表达分析， 脂质标记和异源表达以实现这些目标。对这个过程的了解越来越多 可以帮助开发新的干预措施，以靶向蚊子阶段。