Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
J Immunol. 2010 Nov 15;185(10):6157-67. doi: 10.4049/jimmunol.1001555. Epub 2010 Oct 20.
Abs targeting blood-stage Ags of Plasmodium falciparum are important in acquired immunity to malaria, but major targets remain unclear. The P. falciparum reticulocyte-binding homologs (PfRh) are key ligands used by merozoites during invasion of erythrocytes. PfRh2a and PfRh2b are functionally important members of this family and may be targets of protective immunity, but their potential role in human immunity has not been examined. We expressed eight recombinant proteins covering the entire PfRh2 common region, as well as PfRh2a- and PfRh2b-specific regions. Abs were measured among a cohort of 206 Papua New Guinean children who were followed prospectively for 6 mo for reinfection and malaria. At baseline, Abs were associated with increasing age and active infection. High levels of IgG to all PfRh2 protein constructs were strongly associated with protection from symptomatic malaria and high-density parasitemia. The predominant IgG subclasses were IgG1 and IgG3, with little IgG2 and IgG4 detected. To further understand the significance of PfRh2 as an immune target, we analyzed PfRh2 sequences and found that polymorphisms are concentrated in an N-terminal region of the protein and seem to be under diversifying selection, suggesting immune pressure. Cluster analysis arranged the sequences into two main groups, suggesting that many of the haplotypes identified may be antigenically similar. These findings provide evidence suggesting that PfRh2 is an important target of protective immunity in humans and that Abs act by controlling blood-stage parasitemia and support its potential for vaccine development.
疟原虫裂殖子入侵红细胞过程中所使用的主要配体是 PfRh 家族的 PfRh 红细胞结合同源物。PfRh2a 和 PfRh2b 是 PfRh 家族的重要功能成员，可能是保护性免疫的靶点，但它们在人体免疫中的潜在作用尚未得到检验。我们表达了 8 种重组蛋白，涵盖 PfRh2 共同区域以及 PfRh2a 和 PfRh2b 的特异性区域。我们在巴布亚新几内亚的 206 名儿童队列中测量了抗体，这些儿童前瞻性随访了 6 个月，以检测再感染和疟疾。在基线时，抗体与年龄增长和活动性感染有关。高水平的 IgG 针对所有 PfRh2 蛋白结构，与无症状疟疾和高密度寄生虫血症的保护作用强烈相关。主要 IgG 亚类是 IgG1 和 IgG3，检测到的 IgG2 和 IgG4 较少。为了进一步了解 PfRh2 作为免疫靶标的意义，我们分析了 PfRh2 序列，发现多态性集中在蛋白的 N 端区域，似乎受到多样化选择的影响，表明存在免疫压力。聚类分析将序列分为两个主要组，表明鉴定出的许多单倍型可能具有相似的抗原性。这些发现为 PfRh2 是人类保护性免疫的重要靶点提供了证据，并且 Abs 通过控制血液阶段寄生虫血症来发挥作用，支持其在疫苗开发中的潜力。
