Targeting the Conserved Fusion Loop of HAP2 Inhibits the Transmission of Plasmodium berghei and falciparum.
Targeting the Conserved Fusion Loop of HAP2 Inhibits the Transmission of Plasmodium berghei and falciparum.
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DOI：
10.1016/j.celrep.2017.11.024
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发表时间：
2017-12-05
期刊：
影响因子：
8.8
通讯作者：
Blagborough AM
中科院分区：
文献类型：
--
作者：
Angrisano F;Sala KA;Da DF;Liu Y;Pei J;Grishin NV;Snell WJ;Blagborough AM
抑制疟原虫的传播是消灭疟疾的核心策略，受精过程中配子融合的生物过程是这种方法的一个已被证明的目标。目前抗疟疾疫苗靶点的结构或已知分子功能的缺乏以前一直是传播阻断疫苗开发的障碍。结构/功能研究表明，保守的配子膜融合蛋白HAP 2是II类病毒融合蛋白。在这里，我们表明，针对功能关键网站的融合/CD环与物种特异性抗体减少伯氏疟原虫在体内传输58.9%，在体外受精高达89.9%。在补充性田间研究中观察到恶性疟原虫传播的相应减少（强度/流行率降低75.5%/36.4%）。这些结果强调了Apicomplexa融合的保守机制，同时强调了设计未来抗疟疾传播阻断疫苗的方法。疟原虫HAP 2是一种II类融合蛋白，II类蛋白可靶向抑制受精/传递。合成产生的短肽可诱导传递阻断免疫。发现HAP 2 cd-loop可以作为抗疟疾干预的靶点，在多种疟原虫物种中具有免疫原性，可以诱导特异性识别寄生虫生命周期的性阶段的抗体，并且可以在实验室和现场介导传播阻断免疫。
Inhibiting transmission of Plasmodium is a central strategy in malarial eradication, and the biological process of gamete fusion during fertilization is a proven target for this approach. The lack of a structure or known molecular function of current anti-malarial vaccine targets has previously been a hindrance in the development of transmission-blocking vaccines. Structure/function studies have indicated that the conserved gamete membrane fusion protein HAP2 is a class II viral fusion protein. Here, we demonstrate that targeting a function-critical site of the fusion/cd loop with species-specific antibodies reduces Plasmodium berghei transmission in vivo by 58.9% and in vitro fertilization by up to 89.9%. A corresponding reduction in P. falciparum transmission (75.5%/36.4% reductions in intensity/prevalence) is observed in complimentary field studies. These results emphasize conserved mechanisms of fusion in Apicomplexa, while highlighting an approach to design future anti-malarial transmission-blocking vaccines. Plasmodium HAP2 is a class II fusion protein Class II proteins are targetable to inhibit fertilization/transmission A short synthetically generated peptide can induce transmission-blocking immunity Angrisano et al. find that the HAP2 cd-loop can be targeted as an anti-malarial intervention, is immunogenic across multiple plasmodial species, can induce antibodies that specifically recognize the sexual stages of the parasitic life cycle, and can mediate transmission-blocking immunity in the lab and the field.
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