按蚊中肠共生细菌Serratia sp.阻断疟疾传播的分子机理

Malaria remains one of the world's most devastating vector-born infectious diseases, about 300-500 million people contract the disease annually and more than one million people die of malaria every year. Malaria is still epidemic seriously in some parts of China, with globalization and the frequent international exchanges in recent years, the most deadly Plasmodium falciparum malaria case is growing up 20% annually over the previous year, Continuous emergence and rapid spread of insecticide-resistant mosquitoes and of drug-resistant Plasmodium parasites combined with the lack of an effective vaccine severely limit our ability to fight the disease, new methods to control malaria are urgently needed. The most vulnerable stages of Plasmodium development in the vector mosquito occur in the midgut lumen, where the majority of ingested parasites are killed, making the midgut a prime target for intervention. Several studies have shown that the mosquito midgut microbiota plays an important role in determining vector competence and malaria transmission. However, the exact mechanisms by which the midgut bacteria prevent malaria transmission has not been elucidated. In this study, we will plan to study the newly identified msoquito symbiotic bacterium Serratia sp. that stably colonizes in the midgut, and is able to be transmitted vertically from female to larvae, and significantly inhibits Plasmodium ookinete development. A high throughput screening signature-tagged mutagenesis (STM) assay, combined with in-vivo and in -vitro screening, are implemented to identify genes involved in the ability of Serratia sp. to stably colonize the midgut lumen and inhibit Plasmodium ookinete development, and elucidate molecular mechanisms of the functional genes essential in colonization and anti-parasite development, providing the foundation for exploring the use of symbiotic bacterium to block malaria transmission, and supplying the gene resources for directed genetic modification of gut bacteria, and developing the new weapon to fight malaria. This project will help deepen our understanding of the interaction between gut microbes and insects, and their co-evolution, providing new insights for blocking transmission of other insect-borne diseases.

疟疾是严重危害生命安全的一种无国界的虫媒传染病，全球每年有3-5亿人感染。疟疾仍在我国多地流行，随着全球化和国际交往频繁，近年我国最致命的恶性疟病例以超过20%的速度增加，急需新方法控制疟疾传播。按蚊是疟疾传播媒介，雌蚊中肠是疟原虫发育的最大屏障，大量疟原虫在中肠内被抑制。近来研究表明，按蚊中肠内寄居的共生细菌在抗疟上起重要作用，但其阻断疟疾传播的确切机制尚未阐明。本项目在前期研究基础上，以一株兼具稳定共生和高效抗疟的新共生细菌Serratia sp.为研究对象，利用转座子信号标签构建突变体文库，结合体内和体外筛选，高通量鉴定共生因子和抗疟相关基因，详细揭示Serratia sp.在按蚊中肠内稳定共生和高效抗疟的分子机理，为探索利用共生菌阻断疟疾传播的新策略提供理论依据，为肠道细菌的定向改造提供基因资源，为人类抗疟提供新武器。本项目的研究也将深化对肠道微生物与昆虫相互作用和协同进化的认识。

疟疾是严重危害生命安全的一种的蚊媒传染病，急需新方法控制疟疾传播。疟原虫通过雌性按蚊叮人吸血传播，按蚊中肠是疟原虫发育的最大屏障。肠道菌群是按蚊中肠屏障的重要组成部分，是拮抗疟原虫感染的重要生物因子，但其共生与抗疟机制尚未阐明。我们从按蚊肠道分离到一株高效抗疟的共生细菌沙雷氏菌Serratia AS01，我们在研究中发现AS01具有抗疟作用。我们利用转座子信号标签优化构建了突变体文库，结合体内和体外筛选，鉴定到3个与共生基因；解析了按蚊肠道共生菌沙雷氏菌Serratia AS01的稳定共生和抗疟的分子机制。成功构建出高效抗疟的工程菌株，为利用共生菌阻断疟疾传播提供新策略，为人类抗疟提供新武器。发表标注受本项目资助论文5篇，其中一篇论文发表在Science上。

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