Silvie Olivier, Rubinstein Eric, Franetich Jean-François, Prenant Michel, Belnoue Elodie, Rénia Laurent, Hannoun Laurent, Eling Wijnand, Levy Shoshana, Boucheix Claude, Mazier Dominique
INSERM U511 Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France.
Nat Med. 2003 Jan;9(1):93-6. doi: 10.1038/nm808. Epub 2002 Dec 16.
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. 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, 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.
疟原虫子孢子通过受感染蚊子的叮咬传播，作为疟原虫生命周期的一个必要步骤，首先侵入哺乳动物宿主的肝脏。在肝细胞内，疟原虫子孢子驻留在膜结合的液泡中，在那里它们分化为红外期形式和裂殖子，随后感染红细胞并引发疟疾。疟原虫子孢子靶向肝脏是由主要子孢子表面蛋白、环子孢子蛋白和血小板反应蛋白相关无名蛋白与肝细胞表面的糖胺聚糖特异性结合介导的。然而，子孢子进入肝细胞并在其中分化的分子机制在很大程度上仍然未知。在这里，我们表明四跨膜蛋白CD81（一种丙型肝炎病毒的假定受体）在肝细胞上对于人类恶性疟原虫和啮齿类约氏疟原虫的子孢子感染性是必需的。约氏疟原虫子孢子在体内和体外均无法感染CD81缺陷的小鼠肝细胞，针对小鼠和人类CD81的抗体分别在体外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的需求与子孢子通过形成寄生泡进入肝细胞有关，寄生泡对于寄生虫分化为红外期形式至关重要。
