Program in Molecular Medicine, The Hospital for Sick Children Research Institute, 686 Bay St, Toronto, ON, Canada, M5G 0A4.
Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON, Canada, M5S 1A8.
Nat Commun. 2017 Nov 16;8(1):1568. doi: 10.1038/s41467-017-01924-3.
The Plasmodium falciparum Pfs25 protein (Pfs25) is a leading malaria transmission-blocking vaccine antigen. Pfs25 vaccination is intended to elicit antibodies that inhibit parasite development when ingested by Anopheles mosquitoes during blood meals. The Pfs25 three-dimensional structure has remained elusive, hampering a molecular understanding of its function and limiting immunogen design. We report six crystal structures of Pfs25 in complex with antibodies elicited by immunization via Pfs25 virus-like particles in human immunoglobulin loci transgenic mice. Our structural findings reveal the fine specificities associated with two distinct immunogenic sites on Pfs25. Importantly, one of these sites broadly overlaps with the epitope of the well-known 4B7 mouse antibody, which can be targeted simultaneously by antibodies that target a non-overlapping site to additively increase parasite inhibition. Our molecular characterization of inhibitory antibodies informs on the natural disposition of Pfs25 on the surface of ookinetes and provides the structural blueprints to design next-generation immunogens.
疟原虫恶性疟原虫蛋白 25（Pfs25）是一种主要的疟疾传播阻断疫苗抗原。Pfs25 疫苗接种旨在诱导抗体，当疟原虫在蚊血餐中被按蚊摄入时，抑制寄生虫的发育。Pfs25 的三维结构仍然难以捉摸，这阻碍了对其功能的分子理解，并限制了免疫原的设计。我们报告了通过在人类免疫球蛋白基因座转基因小鼠中用 Pfs25 病毒样颗粒免疫接种来诱导的抗体与 Pfs25 复合物的六个晶体结构。我们的结构研究结果揭示了与 Pfs25 上两个不同免疫原性位点相关的精细特异性。重要的是，其中一个位点与著名的 4B7 小鼠抗体的表位广泛重叠，该抗体可以被靶向非重叠位点的抗体同时靶向，从而相加增加寄生虫抑制。我们对抑制性抗体的分子特征分析阐明了 Pfs25 在卵囊体表面的自然分布，并为设计下一代免疫原提供了结构蓝图。
