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 疟疾是由疟原虫引起的。根据世界卫生组织的说法，那里 2016年，全球有2.16亿人感染这种疾病，导致44.5万人死亡。这种病是这样的 在其全球负担和在根除和消除疟疾的舞台上，它是令人敬畏的，它指出 2015年至2016年间，死于该病的人数仅下降了1000人。此外，第一线的药物 对于简单疟疾的治疗，青蒿素联合疗法开始失败，因为 抗药性疟疾寄生虫的出现，从而在疟疾控制方面取得了巨大的进展 过去的十年可能会在不久的将来被抹去。因此，仍然需要新的干预措施。 疟疾寄生虫有一个复杂的生命周期，就人类疾病而言，这依赖于 既是蚊子媒介，也是人类宿主。蚊子媒介将传染性的子孢子传播给人类 最终导致暴发性血液期感染的宿主，导致所有相关疾病死亡 和发病率。在感染的血液阶段，有性血期的配子体可以通过 蚊子在获取血粉的过程中携带蚊子，在那里它们成熟为配子。配子融合形成一个 受精卵，然后在蚊子中肠内有一个可移动的卵子。动粒细胞穿过中肠上皮细胞 在穿过上皮基底侧并发展为细胞外卵囊之前，即在 与血腔腔及其相关的营养丰富的血淋巴接触。细胞外的生命 环境带来了明显的挑战，人们对卵囊是如何寄生的知之甚少 蚊子寄主，以成熟和释放子孢子，子孢子迁移到唾液腺并等待 传给下一个人类宿主。 研究表明，脂蛋白是一种来自蚊子的脂蛋白复合体 血粉可通过发育卵囊被摄取，其目的可能是为子孢子提供脂质。 制作。然而，卵囊发育是否需要这一过程尚不清楚。我们已经展示了 卵囊表达的三磷酸腺苷结合盒(ABC)转运体在摄取脂蛋白和 编码这种转运蛋白的基因的缺失会导致卵囊发育的严重缺陷，结果 在卵囊成熟度和子孢子释放时间方面明显减少。这项建议旨在充分 阐明ABC转运蛋白在卵囊成熟过程中的作用及其在营养获取中的作用 是生产子孢子所必需的。我们将使用反向遗传学，时空表达分析， 脂质标记和异源表达以实现这些目标。增加对这一过程的了解 可以帮助开发针对疟疾蚊子阶段的新干预措施。