Cytotoxic anti-circumsporozoite antibodies target malaria sporozoites in the host skin
Cytotoxic anti-circumsporozoite antibodies target malaria sporozoites in the host skin
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DOI：
10.1038/s41564-018-0254-z
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发表时间：
2018-11-01
影响因子：
28.3
通讯作者：
Amino, Rogerio
中科院分区：
文献类型：
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作者：
Aliprandini, Eduardo;Tavares, Joana;Amino, Rogerio
疟原虫环子孢子蛋白（CSP）是疟原虫子孢子（SPZ）的主要表面蛋白，SPZ是疟原虫感染蚊虫后在宿主皮肤上产生的运动和侵入阶段的寄生虫。已知针对不同疟原虫物种的中央CSP重复序列的抗体可阻断SPZ感染性（1-5），但这些效应物发挥作用的确切机制尚未完全了解。在这里，使用啮齿动物约氏疟原虫疟疾模型，我们表明抗约氏疟原虫CSP体液免疫介导的无菌保护依赖于寄生虫接种到宿主皮肤中，其中抗体通过特征性的“点状死亡”表型抑制运动并杀死约氏疟原虫SPZ。抗重复单克隆抗体（mAb）的被动转移以补体和Fc受体γ非依赖性方式重现了皮肤接种依赖性保护。这种纯化的mAb还降低运动性，并且特别地，在体外诱导约氏疟原虫SPZ的点状死亡。细胞毒性是物种超越的，因为同源抗CSP重复mAb也杀死伯氏疟原虫和恶性疟原虫SPZ。mAb细胞毒性需要肌动球蛋白马达依赖性移位和保护性CSP表面涂层的剥离，使寄生虫膜对分泌至伤口并穿过宿主细胞膜的SPZ成孔样蛋白敏感（6）。因此，由抗约氏疟原虫CSP重复抗体引起的SPZ适应性的丧失是在宿主皮肤中引发的动态过程，其中SPZ停止移动（7），或迁移并穿过细胞以最终以其自身生命为代价通过宿主组织（7-9）。
The circumsporozoite protein (CSP) is the major surface protein of malaria sporozoites (SPZs), the motile and invasive parasite stage inoculated in the host skin by infected mosquitoes. Antibodies against the central CSP repeats of different plasmodial species are known to block SPZ infectivity(1-5), but the precise mechanism by which these effectors operate is not completely understood. Here, using a rodent Plasmodium yoelii malaria model, we show that sterile protection mediated by anti-P. yoelii CSP humoral immunity depends on the parasite inoculation into the host skin, where antibodies inhibit motility and kill P. yoelii SPZs via a characteristic 'dotty death' phenotype. Passive transfer of an anti-repeat monoclonal antibody (mAb) recapitulates the skin inoculation-dependent protection, in a complement- and Fc receptor gamma-independent manner. This purified mAb also decreases motility and, notably, induces the dotty death of P. yoelii SPZs in vitro. Cytotoxicity is species-transcendent since cognate anti-CSP repeat mAbs also kill Plasmodium berghei and Plasmodium falciparum SPZs. mAb cytotoxicity requires the actomyosin motor-dependent translocation and stripping of the protective CSP surface coat, rendering the parasite membrane susceptible to the SPZ poreforming-like protein secreted to wound and traverse the host cell membrane(6). The loss of SPZ fitness caused by anti-P. yoelii CSP repeat antibodies is thus a dynamic process initiated in the host skin where SPZs either stop moving(7), or migrate and traverse cells to progress through the host tissues(7-9) at the eventual expense of their own life.