Structural and functional basis for inhibition of erythrocyte invasion by antibodies that target Plasmodium falciparum EBA-175.
Structural and functional basis for inhibition of erythrocyte invasion by antibodies that target Plasmodium falciparum EBA-175.
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DOI：
10.1371/journal.ppat.1003390
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Tolia NH
中科院分区：
文献类型：
--
作者：
Chen E;Paing MM;Salinas N;Sim BK;Tolia NH
阻断恶性疟原虫对红细胞的侵袭是一种很有吸引力的抗疟方法。恶性疟原虫EBA-175（PfEBA-175）在入侵期间接合宿主受体血型糖蛋白A（GpA），并且是领先的疫苗候选物。识别PfEBA-175的抗体可以防止寄生虫生长，尽管并非所有抗体都是抑制性的。在这里，使用X-射线晶体学，小角X-射线散射和功能研究，我们报告的结构基础和机制抑制两个PfEBA-175抗体。与PfEBA-175受体结合结构域复合的每种抗体的结构揭示，最有效的抑制性抗体R217接合关键的GpA结合残基和PfEBA-175的拟定二聚体界面。第二种弱抑制性抗体R218与富含天冬酰胺的表面环结合。我们表明，通过结构研究确定的表位是抗体结合的关键。总之，结构和映射研究揭示了不同的作用机制，R217直接阻止受体结合，而R218允许受体结合。使用直接受体结合测定，我们显示R217直接阻断GpA接合，而R218不。我们的研究阐述了PfEBA-175和GpA之间的复杂相互作用，并突出了针对恶性疟原虫侵入红细胞的分子机制的新方法。这些结果表明，旨在通过选择单一或组合多种寄生虫抗原来提高血液阶段疫苗效力的研究应评估对确定的抑制性表位的抗体应答以及对全蛋白抗原的应答。最后，这项工作表明了识别抗原表位和避免诱饵表位在基于抗体的治疗，疫苗和诊断中的重要性。疟疾是一种毁灭性的寄生虫病，每年造成100万人死亡。寄生虫侵入并在红细胞内繁殖，导致疟疾的临床症状。因此，通过疫苗阻止红细胞进入是控制疾病的一种有吸引力的方法。尽管通过识别和结合关键的寄生虫血液阶段蛋白来开发疫苗的广泛努力正在进行中，但疟疾的保护性疫苗已被证明具有挑战性。这部分是因为，虽然寄生虫蛋白质具有引发防止红细胞侵入的抗体的能力，但与产生的无效抗体的总集合相比，这些抗体的比例很小。我们展示了一种防止红细胞侵入的抗体，其靶向红细胞接合所需的关键寄生虫蛋白PfEBA-175的区域。我们还表明，不能阻止红细胞入侵的抗体识别远离PfEBA-175重要功能片段的区域。我们的工作表明，确定抗体靶向的区域，以及抗体预防入侵功能的机制，应该推动未来的疫苗开发和测量当前疫苗组合有效性的研究。
Disrupting erythrocyte invasion by Plasmodium falciparum is an attractive approach to combat malaria. P. falciparum EBA-175 (PfEBA-175) engages the host receptor Glycophorin A (GpA) during invasion and is a leading vaccine candidate. Antibodies that recognize PfEBA-175 can prevent parasite growth, although not all antibodies are inhibitory. Here, using x-ray crystallography, small-angle x-ray scattering and functional studies, we report the structural basis and mechanism for inhibition by two PfEBA-175 antibodies. Structures of each antibody in complex with the PfEBA-175 receptor binding domain reveal that the most potent inhibitory antibody, R217, engages critical GpA binding residues and the proposed dimer interface of PfEBA-175. A second weakly inhibitory antibody, R218, binds to an asparagine-rich surface loop. We show that the epitopes identified by structural studies are critical for antibody binding. Together, the structural and mapping studies reveal distinct mechanisms of action, with R217 directly preventing receptor binding while R218 allows for receptor binding. Using a direct receptor binding assay we show R217 directly blocks GpA engagement while R218 does not. Our studies elaborate on the complex interaction between PfEBA-175 and GpA and highlight new approaches to targeting the molecular mechanism of P. falciparum invasion of erythrocytes. The results suggest studies aiming to improve the efficacy of blood-stage vaccines, either by selecting single or combining multiple parasite antigens, should assess the antibody response to defined inhibitory epitopes as well as the response to the whole protein antigen. Finally, this work demonstrates the importance of identifying inhibitory-epitopes and avoiding decoy-epitopes in antibody-based therapies, vaccines and diagnostics. Malaria is a devastating parasitic disease that kills one million people annually. The parasites invade and multiply within red blood cells, leading to the clinical symptoms of malaria. Therefore, preventing red blood cell, entry through vaccines is an attractive approach to controlling the disease. Although widespread efforts to develop a vaccine by identifying and combining critical parasite blood-stage proteins are underway, a protective vaccine for malaria has proved challenging. This is in part because, while parasite proteins have the ability to elicit antibodies that prevent red blood cell invasion, these antibodies are a small proportion compared to the total collection of ineffective antibodies produced. We show an antibody that prevents red blood cell invasion targets regions of the critical parasite protein PfEBA-175 required for red blood cell engagement. We also show that an antibody that does not prevent red blood cell invasion recognizes a region far removed from important functional segments of PfEBA-175. Our work demonstrates that identifying the regions targeted by antibodies, and the mechanisms by which antibodies that prevent invasion function, should drive future vaccine development and studies measuring the effectiveness of current vaccine combinations.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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影响因子：
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DOI：
10.1073/pnas.1104050108
发表时间：
2011-05-03
影响因子：
11.1
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影响因子：
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作者：
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