Impact of gene-drive systems for population modification on malaria vector mosquitoes

项目摘要 虽然自本世纪之交以来在减少疟疾负担方面取得了重大进展，但上一次 几年来，这一成功和世界卫生组织(世卫组织)在2020年世界大会上的速度有所减速 疟疾报告估计2019年约有2.29亿病例(发病率)和409,000人死亡(死亡率)。 全球约95%的疟疾死亡病例仅发生在31个国家，其中7个在撒哈拉以南非洲。 占所有死亡人数的51%。此外，世界卫生组织预测，如果没有 更多地利用现有技术和开发必要的新工具。世界银行面临的挑战 对新药的持续需求和有效疫苗的缓慢推出使得对新的、 经济有效的疾病控制工具，对人和环境都是安全的。这一需求 为开发控制疟疾寄生虫传播的遗传方法的努力提供了理由。从长远来看， 可持续的基因控制将需要部署旨在应对移民的战略 易受感染的蚊子和寄生虫感染者。用于种群的基因工程蚊子品系 为此目的，改装具有适当的性能特征。野生蚊子迁徙到一个 该地区居住着经过改造的、抗寄生虫的蚊子，将通过与 当地昆虫和携带疟疾的人迁入同一地区将不会感染居民 病媒，因此不是其他人的感染源。我们已经利用了分子 CRISPR/Cas生物学构建位点特异性转基因自主基因驱动系统的机制 蚊子生殖系中的拷贝数扩增。这些驱动系统携带着大量的抗寄生虫药物。 防止携带寄生虫的蚊子传播寄生虫的效应基因。在工作中 假设这些系统将能够影响传播动力学，即使它们提供遗传负载 这会影响生殖健康。我们将调查基因驱动系统插入对 以确定受体蚊子对繁殖成功的影响以及驱动和效应基因的有效性 稳定性。为此，我们的具体目标是：1)评估自主基因驱动系统的影响 冈比亚按蚊繁殖成功的研究。还有一个。Coluzzii和2)评估多代人 冈比亚按蚊自主基因驱动系统的稳定性。还有一个。实验室笼养试验中的coluzzii。 这些具体目标的成功完成将为未来使用这一目标提供计划和模型 疟疾控制中的技术。

Project Summary While significant progress has been made in reducing the malaria burden since the turn of the century, the last few years have seen a deceleration of this success and the World Health Organization (WHO) in its 2020 World Malaria Reportestimates ~229 million cases (morbidity) and 409,000 deaths (mortality) in 2019. Approximately 95% of the global malaria deaths occurred in only 31 countries with seven in sub-Saharan Africa accounting for ~51% of all the deaths. Furthermore, the WHO predicts no further significant decreases without greater use of the existing technologies and the necessary development of new tools. The challenges of the continued demand for new drugs and the slow roll-out of an efficacious vaccine makes urgent the need for new, cost-effective and efficacious disease-control tools that are safe for people and the environment. This need justifies efforts to develop genetic approaches for controlling malaria parasite transmission. Long-term, sustainable genetic control will require the deployment of strategies designed to be resilient to the immigration of susceptible mosquitoes and parasite-infected people. Genetically-engineered mosquito strains for population modification have the appropriate performance features for this purpose. Wild mosquitoes immigrating into a region populated by engineered, parasite-resistant mosquitoes will acquire beneficial genes by mating with the local insects, and persons with malaria moving into the same region will not be able to infect the resident vectors, and therefore are not a source for infection of other people. We have exploited the molecular mechanisms of CRISPR/Cas biology to develop autonomous gene-drive systems for site-specific, transgene copy number amplification in the mosquito germline. These drive systems carry a cargo of anti-parasite effector genes that prevent transmission of the parasites by the mosquitoes carrying them. The working hypothesis is that these systems will be able to impact transmission dynamics even if they confer a genetic load that impacts reproductive fitness. We shall investigate the impact of gene-drive system insertions on the recipient mosquitoes to determine effects on reproductive success and drive and effector gene efficacy and stability. Towards these ends, our Specific Aims are: 1) evaluate the impact of autonomous gene-drive systems on the reproductive success of Anopheles gambiae ss. and An. coluzzii and 2) evaluate the multigenerational stability of autonomous gene-drive systems in Anopheles gambiae ss. and An. coluzzii in laboratory cage trials. The successful completion of these Specific Aims will inform plans and modelling for the future use of this technology in malaria control.