Rhoptry neck protein 4 plays important roles during Plasmodium sporozoite infection of the mammalian liver.
Rhoptry neck protein 4 plays important roles during Plasmodium sporozoite infection of the mammalian liver.
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在侵入过程中，疟原虫从棒状体和微线顶端细胞器分泌蛋白质，这些蛋白质在附着和侵入靶细胞中起关键作用。子孢子阶段特异性基因沉默系统揭示了棒状体颈蛋白2（RON 2），RON 4和RON 5是重要的子孢子入侵蚊子唾液腺。在此，我们进一步研究了RON 4在体内子孢子感染肝脏过程中的作用。在将RON 4敲低的子孢子静脉接种到小鼠体内后，我们证明了子孢子RON 4在子孢子穿越肝窦细胞和感染肝细胞期间具有多种功能。使用肝癌细胞系的体外感染实验显示，分泌的RON 4参与子孢子粘附至肝细胞，并且在肝细胞感染的早期步骤中具有重要作用。此外，在体外运动性测定表明，RON 4是所需的子孢子附着到基板和迁移的开始。这些发现表明RON 4是子孢子通过附着能力和运动性向肝细胞迁移和侵入肝细胞的关键。当子孢子被蚊子接种并通过血流迁移感染肝细胞时，建立了疟疾寄生虫向哺乳动物的传播。支持迁移和细胞侵袭的分子机制的许多方面仍然在很大程度上未阐明。通过在啮齿类疟疾寄生虫伯氏疟原虫中应用子孢子阶段特异性基因沉默系统，我们证明了棒状体颈蛋白4（RON 4）对于体内子孢子感染肝脏至关重要。结合体外研究，发现RON 4在肝感染的早期阶段，通过介导子孢子的粘附能力和运动性的开始，在窦状隙细胞层和侵入肝细胞的交叉过程中发挥作用。由于RON4也在疟原虫裂殖子和弓形虫速殖子中表达，我们的研究结果有助于了解顶复门寄生虫的保守入侵机制。
During invasion, Plasmodium parasites secrete proteins from rhoptry and microneme apical end organelles, which have crucial roles in attaching to and invading target cells. A sporozoite stage-specific gene silencing system revealed that rhoptry neck protein 2 (RON2), RON4, and RON5 are important for sporozoite invasion of mosquito salivary glands. Here, we further investigated the roles of RON4 during sporozoite infection of the liver in vivo. Following intravenous inoculation of RON4-knockdown sporozoites into mice, we demonstrated that sporozoite RON4 has multiple functions during sporozoite traversal of sinusoidal cells and infection of hepatocytes. In vitro infection experiments using a hepatoma cell line revealed that secreted RON4 is involved in sporozoite adhesion to hepatocytes and has an important role in the early steps of hepatocyte infection. In addition, in vitro motility assays indicated that RON4 is required for sporozoite attachment to the substrate and the onset of migration. These findings indicate that RON4 is crucial for sporozoite migration toward and invasion of hepatocytes via attachment ability and motility. Malarial parasite transmission to mammals is established when sporozoites are inoculated by mosquitoes and migrate through the bloodstream to infect hepatocytes. Many aspects of the molecular mechanisms underpinning migration and cellular invasion remain largely unelucidated. By applying a sporozoite stage-specific gene silencing system in the rodent malarial parasite, Plasmodium berghei, we demonstrated that rhoptry neck protein 4 (RON4) is crucial for sporozoite infection of the liver in vivo. Combined with in vitro investigations, it was revealed that RON4 functions during a crossing of the sinusoidal cell layer and invading hepatocytes, at an early stage of liver infection, by mediating the sporozoite capacity for adhesion and the onset of motility. Since RON4 is also expressed in Plasmodium merozoites and Toxoplasma tachyzoites, our findings contribute to understanding the conserved invasion mechanisms of Apicomplexa parasites.
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影响因子：
4
作者：
Combe, Audrey;Moreira, Cristina;Menard, Robert
通讯作者：
Menard, Robert
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影响因子：
1.9
作者：
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通讯作者：
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影响因子：
5.5
作者：
Kanoi, Bernard N.;Takashima, Eizo;Tsuboi, Takafumi
通讯作者：
Tsuboi, Takafumi
影响因子：
5.4
作者：
Frischknecht, Friedrich;Matuschewski, Kai
通讯作者：
Matuschewski, Kai
影响因子：
3
作者：
Beyer K;Kracht S;Kehrer J;Singer M;Klug D;Frischknecht F
通讯作者：
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