Broad dengue neutralization in mosquitoes expressing an engineered antibody
Broad dengue neutralization in mosquitoes expressing an engineered antibody
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DOI：
10.1371/journal.ppat.1008103
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发表时间：
2020-01-01
期刊：
影响因子：
6.7
通讯作者：
Akbari, Omar S.
中科院分区：
文献类型：
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作者：
Buchman, Anna;Gamez, Stephanie;Akbari, Omar S.
由于传统的病媒控制方法在遏制登革热感染方面取得的成功有限，而且世界上一半以上的人口仍处于危险之中，因此需要采取新的战略来减少其对公共卫生的影响。遗传技术的最新进展使人们能够精确修改蚊子的基因组，使它们能够抵抗感染，从而打破传播周期。在这里我们生成了工程Ae。埃及蚊子有效表达DENV靶向单链可变片段（scFv），该单链可变片段来源于先前表征的广泛中和的人抗体，其阻断了这些蚊子中的感染和传播。据我们所知，这是第一个工程转基因的例子，能够使Ae。埃及蚊子对DENV的所有四种血清型100%难治。在未来，基因工程蚊子可以很容易地与基因驱动器配对，能够在整个野生疾病传播蚊子种群中传播转基因，并防止进一步的DENV传播。由于存在许多针对其他虫媒病毒（如基孔肯雅病毒和寨卡病毒）的不同且特征良好的抗体，这项工作也为开发类似的遗传策略以减少这些虫媒病毒的影响提供了概念验证原则。随着登革热病毒（DENV）在全球热带和亚热带地区流行，全球迫切需要有效的策略来控制传播这种疾病的蚊子。基因工程技术的最新进展使人们有可能制造出病媒能力降低的蚊子，从而限制了它们获取和传播病原体的能力。在这里，我们描述了埃及伊蚊蚊子的发展，合成工程，以阻止载体的DENV能力。这些蚊子表达编码源自广泛中和DENV人单克隆抗体的工程化单链可变片段的基因，并且对于所有四种主要抗原性不同的DENV血清型具有显著降低的病毒感染、传播和传播率。重要的是，这是第一种针对所有DENV血清型的工程方法，这对有效抑制疾病至关重要。这些结果为开发有效的基于遗传的DENV控制策略提供了一条引人注目的途径，该策略可以扩展到减少其他虫媒病毒。
Author summary With limited success of traditional vector control methods to curb dengue infections and more than half of the world's population still at risk, there is a need for novel strategies to reduce its impact on public health. Recent advances in genetic technologies has allowed for precise modifications of mosquito genome to make them resistant to infections, thus breaking the transmission cycle. Here we generated engineered Ae. aegypti mosquitoes efficiently expressing a DENV-targeting single-chain variable fragment (scFv) derived from a previously characterized broadly neutralizing human antibody, which blocked infection and transmission in these mosquitoes. To our knowledge, this is the first example of an engineered transgene capable of rendering Ae. aegypti mosquitoes 100% refractory to all four serotypes of DENV. The engineered mosquitoes, in future, could easily be paired with a gene drive, capable of spreading the transgene throughout wild disease-transmitting mosquito populations and preventing further DENV transmission. Since a number of diverse and well-characterized antibodies exist against other arboviruses (eg chikungunya and Zika, this work also provides a proof-of-concept principle for developing similar genetic strategies for reducing the impact of these arboviruses.With dengue virus (DENV) becoming endemic in tropical and subtropical regions worldwide, there is a pressing global demand for effective strategies to control the mosquitoes that spread this disease. Recent advances in genetic engineering technologies have made it possible to create mosquitoes with reduced vector competence, limiting their ability to acquire and transmit pathogens. Here we describe the development of Aedes aegypti mosquitoes synthetically engineered to impede vector competence to DENV. These mosquitoes express a gene encoding an engineered single-chain variable fragment derived from a broadly neutralizing DENV human monoclonal antibody and have significantly reduced viral infection, dissemination, and transmission rates for all four major antigenically distinct DENV serotypes. Importantly, this is the first engineered approach that targets all DENV serotypes, which is crucial for effective disease suppression. These results provide a compelling route for developing effective genetic-based DENV control strategies, which could be extended to curtail other arboviruses.