Determining the interactions between mosquito oogenesis and Plasmodium falciparum survival and transmission

确定蚊子卵子发生与恶性疟原虫存活和传播之间的相互作用

• 批准号: 10189515
• 负责人: Flaminia Catteruccia
• 金额: $ 74.84万
• 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: 2020-06-11 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10189515
• 关键词: Affect; Africa; Africa South of the Sahara; Anopheles Genus; Anopheles gambiae; Apoptosis; Biological Process; Biology; Blood; Burkina Faso; Cell physiology; Cellular Assay; Cessation of life; Coupled; Culicidae; Data; Development; Ecdysterone; Event; Female; Future; Genetic; Genetic Determinism; Genetic Polymorphism; Genotype; Goals; Growth; Hepatocyte; Homeostasis; Human; Impairment; Individual; Infection; Ingestion; Interruption; Investigation; Investments; Knowledge; Link; Lipids; Longevity; Malaria; Measures; Mediating; Metabolic; Midgut; Modeling; Nuclear Receptors; Oocysts; Oogenesis; Output; Ovary; Oxidative Stress; Parasites; Pathway interactions; Periodicity; Physiological; Physiological Processes; Plasmodium; Plasmodium falciparum; Population; Process; RNA Interference; Regulation; Reproduction; Reproductive Process; Role; Salivary Glands; Shapes; Signal Transduction; Sporozoites; Time; Tissues; base; egg; feeding; field study; lipid transport; lipophorin; malaria transmission; male; novel; pressure; reproductive; reproductive fitness; steroid hormone; transcriptome sequencing; transmission process; vector; vector control; vector mosquito

PROJECT ABSTRACT Anopheles gambiae females are the most important vectors of human malaria in sub-Saharan Africa. During their lives, these females feed on blood several times to undergo multiple gonotrophic cycles of egg development and egg laying. These reproductive cycles, largely orchestrated by the steroid hormone 20- hydroxyecdysone (20E), are exploited by Plasmodium falciparum parasites for transmission between human hosts. The time required for parasite development—from ingestion of male and female gametocytes to sporozoite invasion of salivary glands—is called the Extrinsic Incubation Period (EIP) and is a key factor in malaria transmission dynamics, especially when considering the limited lifespan of mosquitoes. Despite its relevance for parasite transmission, the link between parasite development and oogenesis has not been fully explored, and important questions such as whether Plasmodium survival and growth depends on pathways that promote egg development are still largely understudied. In a recent study, we revealed substantial physiological links between P. falciparum development and An. gambiae reproductive processes that shape oogenesis. We have unveiled an unexpected positive correlation between egg and oocyst numbers and have shown that, in instances where 20E function is impaired, reduced oogenesis induces a decrease in parasite intensities. Manipulating egg development by these and other 20E-independent means, however, accelerates Plasmodium growth rates, shortening the EIP and allowing sporozoites to become infectious sooner. Faster growth depends on the accumulation of blood meal-derived midgut lipids trafficked to the ovaries by the lipid transporter Lipophorin (Lp). Our outstanding questions concern the mechanisms by which 20E-regulated oogenetic processes affect parasite numbers, and how the EIP is affected by egg development and Lp-transported lipids in the natural context of multiple gonotrophic cycles. Preliminary evidence suggests that the mis-regulation of 20E signaling may cause parasite death via oxidative stress and/or apoptosis. Moreover, we show that an additional blood meal significantly accelerates parasite growth, while our initial field infections in Burkina Faso suggest the EIP is regulated by parasite genetic determinants. Here we will perform lab and field studies to determine how oogenesis impacts the biology of P. falciparum in the An. gambiae female, from establishment of infection to sporozoite transmission and across multiple reproductive cycles. Specifically, we will: Aim 1) determine the fundamental mechanism by which parasite numbers are reduced when egg development is impaired; Aim 2) analyze how a second gonotrophic cycle affects the EIP and sporozoite infectivity to human hepatocytes; and Aim 3) determine in field infections whether the EIP is regulated by parasite genetic factors. This project will not only fill critical knowledge gaps in mosquito-parasite interactions but will also provide crucial information for control strategies that aim to reduce the reproductive output of mosquito populations.

项目摘要 冈比亚按蚊雌性是撒哈拉以南非洲最重要的人类疟疾病媒。期间 在它们的一生中，这些雌性会多次吸血，以经历卵子的多个生殖营养周期。 发育和产卵。这些生殖周期，主要是由类固醇激素20- 羟基蜕皮激素（20 E）被恶性疟原虫寄生虫利用，用于人与人之间传播 hosts.寄生虫发育所需的时间-从摄取雄性和雌性配子体到 子孢子侵入唾液腺的时间称为外源性潜伏期（EIP），是 疟疾传播动态，特别是考虑到蚊子的寿命有限。尽管 寄生虫传播的相关性，寄生虫发育和卵子发生之间的联系还没有完全 探索，以及重要的问题，如疟原虫的生存和生长是否取决于途径 促进卵子发育的基因还没有被充分研究。 在最近的一项研究中，我们揭示了恶性疟原虫发育和 一个.冈比亚形成卵子发生的生殖过程。我们发现了一个意想不到的积极因素 卵和卵囊数量之间的相关性，并已表明，在20 E功能是 受损的、减少的卵子发生诱导寄生虫强度的降低。控制卵子发育 然而，这些和其他不依赖于20 E的方法加速了疟原虫的生长速率，缩短了疟原虫的寿命。 EIP和允许子孢子更快地变得具有传染性。更快的增长取决于 血液来源的中肠脂质通过脂质转运蛋白（Lp）运输到卵巢。我们 关于20 E调节的卵子发生过程影响寄生虫的机制， 数量，以及EIP如何受到卵子发育和脂蛋白转运脂质的影响， 多个生殖营养周期初步证据表明，20 E信号的错误调节可能 通过氧化应激和/或细胞凋亡引起寄生虫死亡。此外，我们还发现， 显著加速了寄生虫的生长，而我们在布基纳法索的最初现场感染表明， 由寄生虫遗传决定因子调节。在这里，我们将进行实验室和现场研究，以确定如何 卵子发生影响了恶性疟原虫的生物学。冈比亚女性，自成立以来 感染到子孢子传播和跨越多个生殖周期。具体而言，我们将：目标 1)确定寄生虫数量减少的基本机制时，卵发育， 目的2）分析第二生殖周期对EIP和子孢子感染性的影响 目的3）确定在田间感染中EIP是否受寄生虫遗传因子调节。 该项目不仅将填补蚊子-寄生虫相互作用方面的关键知识空白， 这是旨在减少蚊子种群生殖输出的控制战略的关键信息。