Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity
Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity
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DOI：
10.1038/nm808
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发表时间：
2003-01-01
期刊：
影响因子：
82.9
通讯作者：
Mazier, D
中科院分区：
文献类型：
--
作者：
Silvie, O;Rubinstein, E;Mazier, D
疟原虫孢子虫通过受感染蚊子的叮咬传播，首先侵入哺乳动物宿主的肝脏，这是疟原虫生命周期中必不可少的一步。在肝细胞内，疟原虫孢子子驻留在膜结合的液泡中，在那里它们分化为外红细胞形式和分裂子，随后感染红细胞并引起疟疾疾病。靶向肝脏的疟原虫孢子子是通过主要孢子子表面蛋白、环孢子子蛋白和凝血蛋白相关的匿名蛋白特异性结合肝细胞表面的糖胺聚糖介导的(1)。然而，肝细胞内子孢子进入和分化的分子机制在很大程度上是未知的。在这里，我们证明了四跨蛋白CD81，一种假定的丙型肝炎病毒受体(2)，是人类恶性疟原虫和啮齿动物约氏疟原虫孢子虫感染性的肝细胞所必需的。在体内和体外实验中，约氏疟原虫孢子体不能感染缺乏CD81的小鼠肝细胞，抗小鼠和人CD81的抗体在体外分别抑制约氏疟原虫和恶性疟原虫的肝脏发育。我们进一步证明，对CD81的需求与孢子子通过寄生液泡的形成进入肝细胞有关，这是寄生虫向外红细胞形式分化所必需的。
Plasmodium sporozoites are transmitted through the bite of infected mosquitoes and first invade the liver of the mammalian host, as an obligatory step of the life cycle of the malaria parasite. Within hepatocytes, Plasmodium sporozoites reside in a membrane-bound vacuole, where they differentiate into exoerythrocytic forms and merozoites that subsequently infect erythrocytes and cause the malaria disease. Plasmodium sporozoite targeting to the liver is mediated by the specific binding of major sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related anonymous protein, to glycosaminoglycans on the hepatocyte surface(1). Still, the molecular mechanisms underlying sporozoite entry and differentiation within hepatocytes are largely unknown. Here we show that the tetraspanin CD81, a putative receptor for hepatitis C virus(2), is required on hepatocytes for human Plasmodium falciparum and rodent Plasmodium yoelii sporozoite infectivity. P. yoelii sporozoites fail to infect CD81-deficient mouse hepatocytes, in vivo and in vitro, and antibodies against mouse and human CD81 inhibit in vitro the hepatic development of P. yoelii and P. falciparum, respectively. We further demonstrate that the requirement for CD81 is linked to sporozoite entry into hepatocytes by formation of a parasitophorous vacuole, which is essential for parasite differentiation into exoerythrocytic forms.