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

项目摘要 冈比亚按蚊雌性是撒哈拉以南非洲人类疟疾最重要的传播媒介。在.期间 在它们的生活中，这些雌性动物几次以血液为食，经历多次卵子的生殖营养循环 发育和产卵。这些生殖周期，很大程度上是由类固醇激素20- 羟基蜕皮激素(20E)是恶性疟原虫利用的一种在人与人之间传播的基因。 主持人。寄生虫发育所需的时间-从摄入雄配子体和雌配子体到 子孢子侵入唾液腺-被称为外在潜伏期(EIP)，是 疟疾传播动态，特别是在考虑到蚊子寿命有限的情况下。尽管它的 与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不完全 已探索的重要问题，如疟原虫的生存和生长是否依赖于途径 促进卵子发育的物质在很大程度上仍未得到充分的研究。 在最近的一项研究中，我们揭示了恶性疟原虫的发育和 一种。冈比亚的生殖过程塑造了卵子的发生。我们公布了一个意想不到的积极因素 卵子和卵囊数量之间的相关性，并已表明，在20E功能是 卵子发生受损、减少会导致寄生虫强度降低。通过控制卵子的发育 然而，这些和其他与20E无关的方法加速了疟原虫的生长速度，缩短了 EIP，并允许子孢子更快地感染。更快的增长取决于 血粉来源的中肠脂通过脂转运蛋白(LP)运输到卵巢。我们的 悬而未决的问题涉及20E调控的卵子发生过程影响寄生虫的机制 数字，以及在自然环境中，EIP如何受到鸡蛋发育和LP运输脂质的影响 多个促性腺周期。初步证据表明，20E信号的错误调节可能 通过氧化应激和/或细胞凋亡导致寄生虫死亡。此外，我们还表明，额外的血餐 显著加速寄生虫的生长，而我们在布基纳法索的初步田间感染表明EIP是 受寄生虫遗传决定因素的调控。在这里，我们将进行实验室和实地研究，以确定 卵子发生对恶性疟原虫生物学的影响。冈比亚雌性，自成立以来 感染到子孢子传播，并跨越多个生殖周期。具体地说，我们将：目标 1)确定卵子发育时寄生虫数量减少的基本机制 目的2)分析第二个性腺营养周期如何影响EIP和子孢子对人类的感染性 目的3)在田间感染中确定EIP是否受寄生虫遗传因素的调控。 该项目不仅将填补蚊子和寄生虫相互作用方面的关键知识空白，还将提供 为旨在减少蚊子种群繁殖产量的控制战略提供关键信息。

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.