New molecules in malaria sporozoite-hepatocyte infection

描述(由申请人提供)：疟原虫子孢子在感染最终肝细胞之前通过宿主中的几个细胞迁移。我们的初步研究表明，这种迁移对于疟疾的建立是必不可少的，因为：(I)它激活子孢子，使它们有能力入侵肝细胞；(Ii)它激活邻近的肝细胞，使它们容易感染子孢子。我们计划确定寄生虫和宿主细胞在感染的这两个关键方面所涉及的机制和分子。(I)在通过宿主细胞迁移期间，子孢子接触肝细胞的胞浆。这会触发子孢子的胞吐作用，这是感染肝细胞所必需的。使用肝细胞提取物，我们将确定激活子孢子感染的分子，以及这些分子识别的子孢子中的受体。我们还将研究这种激活级联反应导致胞吐的信号转导机制。(Ii)通过宿主肝细胞的迁移诱导肝细胞生长因子(HGF)的释放，从而使肝细胞更容易感染疟原虫。我们将研究HGF介导的肝细胞感染易感性的机制，包括细胞骨架重排、寄生虫空泡的酸化、胆固醇需求和肝细胞凋亡抑制。这项研究的结果将有助于理解介导宿主疟疾发展的第一步：肝细胞感染的分子和细胞机制。新的疟原虫和感染所需的肝细胞因子的特征具有作为疾病控制的新靶点的巨大潜力。

DESCRIPTION (provided by the applicant): Plasmodium sporozoites migrate through several cells in the host before infecting a final hepatocyte. Our Preliminary Studies show that this migration is essential for the establishment of malaria because; (i) it activates sporozoites making them competent for hepatocyte invasion; (ii) it activates neighboring hepatocytes making them susceptible for sporozoite infection. We plan to identify parasite and host cell mechanisms and molecules involved in these two crucial aspects of infection. (i) During migration through host cells sporozoites contact the cytosol of hepatocytes. This triggers exocytosis in sporozoites that is required for infection of hepatocytes. Using hepatocyte extracts we will identify the molecules that activate sporozoites for infection and the receptors that these molecules recognize in the sporozoite. We will also study the mechanism of signal transduction of this activation cascade resulting in exocytosis. (ii) Migration through host hepatocytes induces the release of hepatocyte growth factor (HGF) that makes hepatocytes susceptible for Plasmodium infection. We will investigate the mechanisms underlying HGF-mediated hepatocyte susceptibility for infection, including cytoskeletal rearrangements, acidification of the parasitophorous vacuole, cholesterol requirement, and hepatocyte apoptosis inhibition. Results from this study will contribute to the understanding of the molecular and cellular mechanisms mediating the first step of malaria development in the host: the infection of hepatocytes. The characterization of novel Plasmodium and hepatocyte factors that is required for infection hold significant potential as novel targets for disease control.