TRAP AS A CANDIDATE MALARIA VACCINE

描述（改编自研究者摘要）：大量证据 在啮齿动物模型和人类志愿者中显示， 疟疾子孢子的感染可以通过含有 环子孢子蛋白（CS）是子孢子的主要表面蛋白。 CS蛋白通过其区域II-+基序参与粘附 寄生虫侵入肝细胞的步骤。 研究者 发现另一种子孢子膜蛋白，血小板反应蛋白相关的 匿名蛋白（TRAP），是额外需要的感染性：TRAP (-)寄生虫没有表现出特征性的滑行运动， Apicomplexa，不感染蚊子的唾液腺或 哺乳动物宿主的肝脏。 TRAP基因编码一种典型的膜 具有肽锚和胞质结构域的蛋白质。 n-末端 TRAP的区域包含约220个残基模块， 与在一个或多个整合素中发现的A结构域（或整合素的I结构域）同源， 大量蛋白质中的拷贝参与细胞-细胞，细胞-基质 交互. 高分辨率晶体结构的A域的 整联蛋白揭示了表面暴露的金属离子依赖性 参与蛋白质识别的粘附位点（MIDAS） 配体。 长期目标是分析结构/功能 TRAP的特性，并使用这些信息来提高 CS疫苗。 具体目的是：1）通过基因打靶获得 伯氏疟原虫品系具有氨基酸TRAP的微小突变， 推测与金属离子配位，而伯氏疟原虫中的缺失线 TRAP的胞质结构域。 2)研究这些突变体的表型 蚊媒和哺乳动物宿主中的寄生虫。 3)表达本土 和伯氏疟原虫TRAP的A结构域的突变形式，研究它们的 结合金属离子，并抑制子孢子侵入体外肝细胞。 4)开发合成疫苗， 表面暴露的环路可能位于A的MIDAS边缘 约氏疟原虫TRAP的结构域。

DESCRIPTION (adapted from investigators abstract): A large body of evidence in rodent models and in human volunteers shows that protection against infection by malaria sporozoites can be obtained by vaccines containing the circumsporozoite (CS) protein, the major surface protein of sporozoites. Through its region II-plus motif, CS protein participates in the attachment step of the invasion of hepatocytes by the parasites. The investigator finds that another sporozoite membrane protein, the thrombospondin-related anonymous protein (TRAP), is additionally required for infectivity: TRAP (-) parasites do not exhibit the characteristic gliding motility of Apicomplexa, and do not infect the salivary glands of mosquitoes or the liver of the mammalian host. The TRAP gene encodes a typical membrane protein with a peptide anchor and a cytoplasmic domain. The N-terminal region of TRAP contains an approximately 220 residue module that is homologous to the A domains (or I domain of integrins) found in one or more copies in a large number of proteins involved in cell-cell, cell-matrix interactions. The high resolution crystal structure of A domains of integrins reveals the presence of a surface exposed metal ion dependent adhesion site (MIDAS) that participates in the recognition of the protein ligands. The long term objectives are to analyze the structural/functional properties of TRAP, and to use this information to improve the efficacy of CS vaccines. The specific aims are 1) to obtain by gene targeting Plasmodium berghei lines with subtle mutations in TRAP of amino acids that are presumed to coordinate metal ion, and P. berghei lines with deletions in the cytoplasmic domain of TRAP. 2) to study the phenotype of these mutant parasites in the mosquito vector and mammalian host. 3) to express native and mutant forms of the A domain of P. berghei TRAP, study their ability to bind metal ions, and to inhibit sporozoite invasion of hepatocytes in vitro. 4) to develop synthetic vaccines that elicit specific antibodies against surface-exposed loops presumably located at the edges of the MIDAS of the A domain of P. yoelii TRAP.