Mechanisms of nutrient acquisition by malaria parasite mosquito stages

项目总结和摘要 疟原虫引起疟疾。根据世界卫生组织的数据， 全世界有2.16亿病例，2016年导致44.5万人死亡。因此，该疾病 在全球范围内以及在根除和消灭疟疾的竞技场中， 在2015年至2016年期间，该疾病的死亡人数仅下降了1000人。此外，一线药物 治疗无并发症疟疾的青蒿素联合疗法开始失败， 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进展， 在不久的将来，过去十年可能会被消灭。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，在人类疾病的情况下，这依赖于 蚊子和人类的宿主。蚊媒将传染性子孢子传播给人类 最终导致爆发性血液期感染的宿主，该感染导致所有相关疾病死亡 和发病率。在感染的血液阶段，性血阶段的配子体可以通过 蚊子在吸血过程中传播媒介，在那里它们成熟为配子。配子融合形成 受精卵，然后是蚊子中肠内的能动动合子。动合子穿过中肠上皮细胞 在通过上皮的基底侧排出并发育为细胞外卵囊之前， 与血体腔及其相关的营养丰富的血淋巴接触。细胞外的生命 环境提出了不同的挑战，而且很少有人知道卵囊是如何寄生在其体内的。 蚊子宿主，以便成熟并释放子孢子，子孢子迁移到唾液腺并等待 以便传染给下一个人类宿主 研究表明，来自蚊子的脂蛋白复合物， 血粉可以被发育中的卵囊吸收，可能是为了给子孢子提供脂质 生产然而，这一过程是否是卵囊发育所必需的尚不清楚。我们已经表明 卵囊表达的ATP结合盒（ABC）转运蛋白在脂转运蛋白的摄取中起作用， 编码这种转运蛋白的基因的缺失导致卵囊发育的严重缺陷， 卵囊成熟和子孢子释放时间显著减少。该提案旨在充分 阐明ABC转运蛋白在卵囊成熟中的作用及其参与营养物质的获取 是子孢子产生所必需的。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来实现这些目标。对这一过程的更多了解 可以帮助开发针对疟疾蚊子阶段的新干预措施。

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.