Components of the Medea gene drive system in a mosquito Aedes aegypti

蚊子传播的病毒性疾病，如登革热、基孔肯雅热、黄热病和寨卡病毒，仍然是一个主要的国际公共卫生问题。尽管采取了控制措施，但感染人数仍在增加，这表明现有的依赖于抑制蚊虫媒介种群的控制策略并不有效。埃及伊蚊（Aedes aegypti）是这些病毒感染的主要原因，很难用常规工具加以控制。它在各种各样的人造容器中繁殖，通常是隐蔽的，雌性在白天叮咬，这使得它们的杀虫剂非常具有挑战性。此外，伊蚊对杀虫剂的抗性增强。埃及伊蚊的数量进一步加剧了这一局势。为了减轻疾病负担，人们提出了新的基因控制策略，旨在抑制蚊子种群或通过释放无法传播病毒的工程蚊子来改造蚊子种群。后一种策略要想有效，就需要一种机制，使抗病原体合成构建物能够在整个蚊子种群中迅速传播。一种名为美狄亚（Medea）的基因驱动机制，迄今为止只在黑胃果蝇（Drosophila melanogaster）中构建，已被证明具有所需的侵入性。由于蚊虫发育生物学方面的相关信息仍然缺乏，因此开发蚊子功能性美狄亚因子的努力尚未取得成功。在这项研究中，我们将重点阐明卵子生产和Ae早期卵巢中发生的关键发育过程。以确定最理想的遗传成分美狄亚元件在该蚊种功能。鉴定出的序列将分别在转基因蚊子系中进行验证，并随后用于在伊蚊中创建一个原理证明功能的美狄亚基因驱动。

Mosquito-borne viral diseases, such as dengue, chikungunya, yellow fever, and Zika continue to be a major international public health problem. Despite control efforts, the numbers of infections are on the increase, which indicates that the existing control strategies, relying on suppression of mosquito vector populations, are not effective. The mosquito Aedes aegypti, responsible for the great majority of infections with these viruses, is difficult to control with the conventional tools. It breeds in various, often cryptic, man-made containers, and their females bite during the day, making their targeting with insecticides very challenging. Moreover, increasing resistance to insecticides in the Ae. aegypti populations further exacerbates the situation. To reduce disease burden, new genetic control strategies have been proposed, aiming at suppression of mosquito populations or at mosquito population modification by releasing engineered mosquitoes incapable of virus transmission. The latter strategies, to be effective, require a mechanism that would allow a rapid spread of the anti-pathogen synthetic constructs through the entire mosquito populations. A gene drive mechanism, called Medea, constructed thus far only in a fruit fly Drosophila melanogaster, has been demonstrated to possess the required invasive properties. Efforts to develop functional Medea element in mosquitoes have not yet met with success, because information about the relevant aspects of mosquito developmental biology is still lacking. In this study, we will focus on elucidation of the key developmental processes occurring in ovaries during egg production and in early Ae. aegypti embryos to identify the most optimal genetic constituents of the Medea element functional in this mosquito species. The identified sequences will be individually validated in transgenic mosquito lines and, subsequently used for the creation of a proof-of-principle functional Medea gene drive in Aedes.