Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12734-9. doi: 10.1073/pnas.1204158109. Epub 2012 Jul 16.
The most vulnerable stages of Plasmodium development occur in the lumen of the mosquito midgut, a compartment shared with symbiotic bacteria. Here, we describe a strategy that uses symbiotic bacteria to deliver antimalaria effector molecules to the midgut lumen, thus rendering host mosquitoes refractory to malaria infection. The Escherichia coli hemolysin A secretion system was used to promote the secretion of a variety of anti-Plasmodium effector proteins by Pantoea agglomerans, a common mosquito symbiotic bacterium. These engineered P. agglomerans strains inhibited development of the human malaria parasite Plasmodium falciparum and rodent malaria parasite Plasmodium berghei by up to 98%. Significantly, the proportion of mosquitoes carrying parasites (prevalence) decreased by up to 84% for two of the effector molecules, scorpine, a potent antiplasmodial peptide and (EPIP)(4), four copies of Plasmodium enolase-plasminogen interaction peptide that prevents plasminogen binding to the ookinete surface. We demonstrate the use of an engineered symbiotic bacterium to interfere with the development of P. falciparum in the mosquito. These findings provide the foundation for the use of genetically modified symbiotic bacteria as a powerful tool to combat malaria.
疟原虫发育的最脆弱阶段发生在蚊子中肠的腔中，这是与共生细菌共享的隔室。在这里，我们描述了一种利用共生细菌将抗疟效应分子递送到中肠腔中的策略，从而使宿主蚊子对疟疾感染具有抗性。我们使用大肠杆菌溶血素 A 分泌系统促进了成团泛菌（一种常见的蚊子共生细菌）分泌多种抗疟原虫效应蛋白。这些经过工程改造的成团泛菌菌株可将人类疟原虫疟原虫和啮齿动物疟原虫疟原虫的发育抑制高达 98%。重要的是，两种效应分子中的两种（蝎素，一种有效的抗疟肽和（EPIP）（4），四个拷贝的疟原虫烯醇酶-纤溶酶原相互作用肽可防止纤溶酶原与动合子表面结合）的寄生虫携带率（流行率）降低了 84%。我们证明了利用工程共生细菌来干扰蚊子中疟原虫的发育。这些发现为利用基因修饰共生细菌作为对抗疟疾的强大工具提供了基础。
