Antibodies against thrombospondin-related anonymous protein do not inhibit Plasmodium sporozoite infectivity in vivo
Antibodies against thrombospondin-related anonymous protein do not inhibit Plasmodium sporozoite infectivity in vivo
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DOI：
10.1128/iai.68.6.3667-3673.2000
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发表时间：
2000-06-01
影响因子：
3.1
通讯作者：
Nussenzweig, V
中科院分区：
文献类型：
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作者：
Gantt, S;Persson, C;Nussenzweig, V
血栓反应蛋白相关匿名蛋白（TRAP）是一种候选疟疾疫苗抗原，是疟原虫孢子体滑行运动和细胞侵袭所必需的。首次详细评价了抗TRAP抗体在体内抑制孢子虫感染性的能力。TRAP包含一个a结构域，这是一个在整合素中发现的特征良好的粘附基元。我们在这里模拟了约氏疟原虫TRAP a结构域的三维结构，并定位了MIDAS（金属离子依赖粘附位点）周围的区域，MIDAS是该结构域的假定业务端。用含有这些a结构域的结构体对小鼠进行免疫，但不能保护小鼠免受孢子虫的攻击。此外，针对TRAP的a结构域、保守N端和重复区域的单克隆抗体和兔多克隆抗体对小鼠的滑动运动性和孢子体传染性没有影响。TRAP位于顶复合体寄生虫的分泌细胞器微细胞中。因此，这里测试的抗体通过免疫荧光染色细胞质TRAP明亮。然而，在孢子体表面很少检测到TRAP，相反，当孢子体被钙离子载体处理时，TR - IP在寄生虫表面发生了戏剧性的重新定位，这可能模拟了孢子体在体内接触其靶细胞时微分子释放TRAP的过程。与培养的肝癌细胞接触似乎也会诱导TRAP释放到孢子体表面，如果大量TRAP在其细胞受体附近释放，则抗体可能难以实现有效的竞争性抑制。
Thrombospondin-related anonymous protein (TRAP), a candidate malaria vaccine antigen, is required for Plasmodium sporozoite gliding motility and cell invasion. For the first time, the ability of antibodies against TRAP to inhibit sporozoite infectivity in vivo is evaluated in detail. TRAP contains an A-domain, a well-characterized adhesive motif found in integrins, We modeled here a three-dimensional structure of the TRAP A-domain of Plasmodium yoelii and located regions surrounding the MIDAS (metal ion-dependent adhesion site), the presumed business end of the domain. Mice were immunized,vith constructs containing these A-domain regions but were not protected from sporozoite challenge. Furthermore, monoclonal and rabbit polyclonal antibodies against the A-domain, the conserved N terminus, and the repeat region of TRAP had no effect on the gliding motility or sporozoite infectivity to mice. TRAP is located in micronemes, secretory organelles of apicomplexan parasites. Accordingly, the antibodies tested here stained cytoplasmic TRAP brightly by immunofluorescence. However, very little TRAP could be detected on the surface of sporozoites, In contrast, a dramatic relocalization of TR IP onto the parasite surface occurred when sporozoites were treated with calcium ionophore, This likely mimics the release of TRAP from micronemes when a sporozoite contacts its target cell in vivo. Contact with hepatoma cells in culture also appeared to induce the release of TRAP onto the surface of sporozoites, If large amounts of TRAP are released in close proximity to its cellular receptor(s), effective competitive inhibition by antibodies may be difficult to achieve.