Fetuin-A, a hepatocyte-specific protein that binds Plasmodium berghei thrombospondin-related adhesive protein:: a potential role in infectivity
Fetuin-A, a hepatocyte-specific protein that binds Plasmodium berghei thrombospondin-related adhesive protein:: a potential role in infectivity
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DOI：
10.1128/iai.73.9.5883-5891.2005
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发表时间：
2005-09-01
影响因子：
3.1
通讯作者：
Sultan, AA
中科院分区：
文献类型：
--
作者：
Jethwaney, D;Lepore, T;Sultan, AA
当昆虫媒介将疟原虫的子孢子注射到敏感的脊椎动物宿主中时，疟疾感染就开始了。子孢子迅速离开循环系统入侵肝细胞，在那里进一步发展产生在红细胞内入侵和繁殖的寄生虫形式。以往的实验表明，凝血酶敏感蛋白相关黏附蛋白(TRAP)在子孢子对肝细胞的感染性中起重要作用。TRAP是一种典型的1型跨膜蛋白，其胞外区较长，含有A区和凝血酶反应蛋白重复序列两个粘附区。我们已经获得了TRAP粘附域的重组蛋白。这些TRAP片段与肝细胞直接相互作用，并在体外抑制子孢子的侵袭。当重组的TRAP A结构域用于针对肝细胞膜组分的免疫沉淀时，它与与细胞外基质相关的肝细胞特异性蛋白α2-Heremans-Schmid糖蛋白/胎儿蛋白-A结合。当可溶性子孢子蛋白部分被免疫沉淀在胎球蛋白-A吸附的蛋白A柱上时，TRAP结合了该配体。重要的是，抗胎蛋白-A抗体抑制了子孢子对肝细胞的入侵。此外，与野生型C57BL/6小鼠相比，胎球蛋白A缺陷小鼠在伯氏疟原虫子孢子攻击下，疟疾感染的发病时间延迟。这些数据表明，TRAP的胞外区与肝细胞膜上的胎球蛋白-A相互作用，这种相互作用增强了寄生虫入侵肝细胞的能力。
Malaria infection is initiated when the insect vector injects Plasmodium sporozoites into a susceptible vertebrate host. Sporozoites rapidly leave the circulatory system to invade hepatocytes, where further development generates the parasite form that invades and multiplies within erythrocytes. Previous experiments have shown that the thrombospondin-related adhesive protein (TRAP) plays an important role in sporozoite infectivity for hepatocytes. TRAP, a typical type-1 transmembrane protein, has a long extracellular region, which contains two adhesive domains, an A-domain and a thrombospondin repeat. We have generated recombinant proteins of the TRAP adhesive domains. These TRAP fragments show direct interaction with hepatocytes and inhibit sporozoite invasion in vitro. When the recombinant TRAP A-domain was used for immunoprecipitation against hepatocyte membrane fractions, it bound to alpha 2-Heremans-Schmid glycoprotein/fetuin-A, a hepatocyte-specific protein associated with the extracellular matrix. When the soluble sporozoite protein fraction was immunoprecipitated on a fetuin-A-adsorbed protein A column, TRAP bound this ligand. Importantly, anti-fetuin-A antibodies inhibited invasion of hepatocytes by sporozoites. Further, onset of malaria infection was delayed in fetuin-A-deficient mice compared to that in wild-type C57BL/6 mice when they were challenged with Plasmodium berghei sporozoites. These data demonstrate that the extracellular region of TRAP interacts with fetuin-A on hepatocyte membranes and that this interaction enhances the parasite's ability to invade hepatocytes.