An inhibitory antibody blocks interactions between components of the malarial invasion machinery.
An inhibitory antibody blocks interactions between components of the malarial invasion machinery.
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DOI：
10.1371/journal.ppat.1000273
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发表时间：
2009-01
期刊：
影响因子：
6.7
通讯作者：
Blackman, Michael J.
中科院分区：
文献类型：
--
作者：
Collins, Christine R.;Withers-Martinez, Chrislaine;Hackett, Fiona;Blackman, Michael J.
顶复门病原体（例如疟疾寄生虫疟原虫属）对宿主细胞的入侵。弓形虫涉及从称为微线体和棒状体的分泌细胞器中释放蛋白质。在弓形虫中，一种蛋白质复合物包含微线体顶膜抗原 1 (AMA1)、两种棒状体颈蛋白和一种名为 Ts4705 的蛋白质，定位于移动连接处，即入侵期间寄生虫和宿主细胞之间紧密相连的区域。 AMA1 抗体可防止侵袭并在体内具有保护作用，因此 AMA1 作为候选疟疾疫苗受到广泛关注。在这里，我们报告在弓形虫中发现的 AMA1 复合物在恶性疟原虫中是保守的。我们证明，当 PfAMA1 与其伙伴蛋白形成复合物时，识别恶性疟原虫 AMA1 (PfAMA1) 的侵袭抑制单克隆抗体 (mAb) 4G2 无法结合。我们进一步表明，复合物的形成需要一个完全保守的 PfAMA1 残基 Tyr251，位于与 mAb 4G2 表位相邻的保守疏水沟内。我们认为 mAb 4G2 通过阻止 PfAMA1 与入侵复合物的其他成分相互作用来抑制入侵。我们的研究结果应该有助于基于 PfAMA1 的亚单位疟疾疫苗的合理设计。疟疾是由单细胞寄生虫侵入红细胞内并在红细胞内生长引起的。许多可用的抗疟药物越来越无效，而且还没有疫苗。某些疟疾蛋白会诱导保护性抗体反应，防止红细胞入侵。这项研究的重点是一种名为 4G2 的抗体（专门针对一种名为 AMA1 的寄生虫蛋白）防止入侵的机制。就在入侵之前，AMA1 被释放到寄生虫表面，在称为“移动连接”的瞬时结构中与其他寄生虫蛋白相互作用，寄生虫在进入细胞时通过该结构移动。我们已经鉴定出恶性疟原虫中这种蛋白质复合物的所有成分，恶性疟原虫是最危险的疟疾的病原体。我们发现，虽然 4G2 可以与游离的 AMA1 结合，但当 AMA1 与其伴侣蛋白形成复合物时，4G2 就无法结合。这表明在入侵之前抗体的结合阻止了复合物的组装。为了支持这一点，我们发现 AMA1 表面“疏水槽”内的氨基酸非常接近 4G2 识别的位点，参与 AMA1 复合物的形成。这些发现提出了基于 AMA1 优化设计抗疟疫苗的方法。
Host cell invasion by apicomplexan pathogens such as the malaria parasite Plasmodium spp. and Toxoplasma gondii involves discharge of proteins from secretory organelles called micronemes and rhoptries. In Toxoplasma a protein complex comprising the microneme apical membrane antigen 1 (AMA1), two rhoptry neck proteins, and a protein called Ts4705, localises to the moving junction, a region of close apposition between parasite and host cell during invasion. Antibodies against AMA1 prevent invasion and are protective in vivo, and so AMA1 is of widespread interest as a malaria vaccine candidate. Here we report that the AMA1 complex identified in Toxoplasma is conserved in Plasmodium falciparum. We demonstrate that the invasion-inhibitory monoclonal antibody (mAb) 4G2, which recognises P. falciparum AMA1 (PfAMA1), cannot bind when PfAMA1 is in a complex with its partner proteins. We further show that a single completely conserved PfAMA1 residue, Tyr251, lying within a conserved hydrophobic groove adjacent to the mAb 4G2 epitope, is required for complex formation. We propose that mAb 4G2 inhibits invasion by preventing PfAMA1 from interacting with other components of the invasion complex. Our findings should aid the rational design of subunit malaria vaccines based on PfAMA1. Malaria is caused by a singe-celled parasite that invades and grows within red blood cells. Many available antimalarial drugs are increasingly ineffective, and there is no vaccine. Certain malarial proteins induce protective antibody responses that prevent red cell invasion. This study focuses on the mechanism by which an antibody called 4G2, specific for a parasite protein called AMA1, prevents invasion. Just before invasion, AMA1 is discharged onto the parasite surface, where it interacts with other parasite proteins at a transient structure called the ‘moving junction’, through which the parasite moves as it enters the cell. We have identified all the components of this protein complex in Plasmodium falciparum, the causative agent of the most dangerous form of malaria. We show that whereas 4G2 can bind to free AMA1, it cannot bind when AMA1 is in a complex with its partner proteins. This suggests that antibody binding just before invasion prevents assembly of the complex. In support of this, we show that amino acids within a surface-located ‘hydrophobic trough’ on AMA1, very close to the site recognised by 4G2, are involved in formation of the AMA1 complex. These findings suggest ways in which to optimally design antimalarial vaccines based on AMA1.
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影响因子：
4.8
作者：
Bradley, PJ;Ward, C;Boothroyd, JC
通讯作者：
Boothroyd, JC
恶性疟原虫裂殖子中棒状体颈蛋白 RON2 与微线体蛋白 AMA1 形成复合物
影响因子：
1.9
作者：
Cao, Jun;Kaneko, Osamu;Torii, Motomi
通讯作者：
Torii, Motomi
影响因子：
4.8
作者：
Howell, SA;Wells, I;Blackman, MJ
通讯作者：
Blackman, MJ
影响因子：
3.3
作者：
Mital, J;Meissner, M;Ward, GE
通讯作者：
Ward, GE
影响因子：
--
作者：
Alexander, David L.;Arastu-Kapur, Shirin;Boothroyd, John C.
通讯作者：
Boothroyd, John C.