Identification and Characterization of Functional Human Monoclonal Antibodies to Plasmodium vivax Duffy-Binding Protein
Identification and Characterization of Functional Human Monoclonal Antibodies to Plasmodium vivax Duffy-Binding Protein
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DOI：
10.4049/jimmunol.1801631
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发表时间：
2019-05-01
影响因子：
4.4
通讯作者：
King, Christopher L.
中科院分区：
文献类型：
--
作者：
Carias, Lenore L.;Dechavanne, Sebastien;King, Christopher L.
间日疟原虫侵入网织红细胞依赖于寄生虫和宿主红细胞之间独特的受体-配体相互作用。间日疟原虫Duffy结合蛋白（DBPII）的高度多态性结构域II与红细胞的Duffy Ag趋化因子受体（DARC）的结合是必不可少的。一些暴露于间日疟原虫的个体获得了阻断DBPIIDARC相互作用并抑制间日疟原虫网织红细胞侵袭的DBPII抗体，并且Ab水平与针对间日疟原虫疟疾的保护相关。为了更好地理解保护性人Ab对DBPII的功能特征和良好特异性，我们从三个具有对DBPII的高阻断活性的个体中分选单个DBPII特异性IgG（+）记忆B细胞。我们从阻断DBPII-DARC结合的不同谱系中鉴定了12种DBPII特异性人mAb。所有mAb均为间日疟原虫菌株，其超越并靶向DBPII与DARC的已知结合基序。11个mAb相互竞争结合，表明识别相同或重叠的表位。自然获得的阻断抗体DBPII从个人居住在不同的P间日疟原虫流行地区的高水平与单克隆抗体竞争，这表明广泛共享的识别位点。我们还发现mAb在体外抑制间日疟原虫进入网织红细胞。这些发现表明，IgG（+）记忆B细胞活性的个人与P间日疟原虫菌株超越抗体DBPII显示有限的克隆反应与抑制性阻断针对一个独特的区域的分子。
Plasmodium vivax invasion of reticulocytes relies on distinct receptor-ligand interactions between the parasite and host erythrocytes. Engagement of the highly polymorphic domain II of the P. vivax Duffy-binding protein (DBPII) with the erythrocyte's Duffy Ag receptor for chemokines (DARC) is essential. Some P vivax-exposed individuals acquired Abs to DBPII that block DBPIIDARC interaction and inhibit P vivax reticulocyte invasion, and Ab levels correlate with protection against P. vivax malaria. To better understand the functional characteristics and fine specificity of protective human Abs to DBPII, we sorted single DBPII-specific IgG(+) memory B cells from three individuals with high blocking activity to DBPII. We identified 12 DBPII-specific human mAbs from distinct lineages that blocked DBPII-DARC binding. All mAbs were P. vivax strain transcending and targeted known binding motifs of DBPII with DARC. Eleven mAbs competed with each other for binding, indicating recognition of the same or overlapping epitopes. Naturally acquired blocking Abs to DBPII from individuals with high levels residing in different P vivax- endemic areas worldwide competed with mAbs, suggesting broadly shared recognition sites. We also found that mAbs inhibited P. vivax entry into reticulocytes in vitro. These findings suggest that IgG(+) memory B cell activity in individuals with P vivax strain- transcending Abs to DBPII display a limited clonal response with inhibitory blocking directed against a distinct region of the molecule.