A Plasmodium sporozoite protein with a membrane attack complex domain is required for breaching the liver sinusoidal cell layer prior to hepatocyte infection
A Plasmodium sporozoite protein with a membrane attack complex domain is required for breaching the liver sinusoidal cell layer prior to hepatocyte infection
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DOI：
10.1111/j.1462-5822.2004.00447.x
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发表时间：
2005-02-01
影响因子：
3.4
通讯作者：
Yuda, M
中科院分区：
文献类型：
--
作者：
Ishino, T;Chinzei, Y;Yuda, M
疟原虫子孢子在蚊子吸血期间被注射到哺乳动物宿主中，并由血流携带到肝脏，在那里它们感染肝细胞并发育成侵入红细胞的形式。为了到达肝细胞，子孢子必须穿过肝窦细胞层，肝窦细胞层将肝细胞与循环系统分开。关于子孢子突破这一细胞屏障的分子机制知之甚少。在这里，我们报告，一个蛋白质与膜攻击复合物/穿孔素（MACPF）相关的结构域参与这一步骤。该分子特异性表达于肝脏感染的子孢子中，并定位于参与宿主细胞侵袭的微丝细胞器中。基因破坏实验表明，这种蛋白质是必不可少的子孢子的膜损伤活性，并参与其遍历肝细胞感染前的窦状细胞层。干扰物无法离开循环，其中大部分通过肝脏灌注从血液中消除。我们的研究结果表明，该分子的孔形成活性的宿主质膜的破裂是必要的子孢子的细胞通道。这份报告是第一次证明一个重要的作用，MACPF相关蛋白在宿主细胞入侵的病原微生物。
Plasmodium sporozoites are injected into the mammalian host during mosquito blood feeding and carried by the blood stream to the liver, where they infect hepatocytes and develop into erythrocyte-invasive forms. To reach the hepatocytes, sporozoites must cross the liver sinusoidal cell layer, which separates the hepatocytes from the circulatory system. Little is known about the molecular mechanisms by which sporozoites breach this cellular barrier. Here we report that a protein with a membrane attack complex/perforin (MACPF)-related domain is involved in this step. This molecule is specifically expressed in liver-infective sporozoites and localized in micronemes, organelles engaged in host cell invasion. Gene disruption experiments revealed that this protein is essential for the membrane-wounding activity of the sporozoite and is involved in its traversal of the sinusoidal cell layer prior to hepatocyte-infection. Disruptants failed to leave the circulation, and most of them were eliminated from the blood by liver perfusion. Our results suggest that rupture of the host plasma membrane by the pore-forming activity of this molecule is essential for cell passage of the sporozoite. This report is the first to demonstrate an important role of a MACPF-related protein in host cell invasion by a pathogenic microorganism.