New molecules in malaria sporozoite-hepatocyte infection

在感染最终的肝细胞之前，疟原虫的子孢子通过宿主中的几个细胞迁移。我们的 初步研究表明，这种迁徙对疟疾的形成至关重要，因为： 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的机制和涉及这两个关键方面的分子 感染的可能性。(I)在通过宿主细胞迁移期间，子孢子接触肝细胞的胞浆。 触发感染肝细胞所需的子孢子的胞吐作用。使用肝细胞提取液 将确定激活感染的子孢子的分子以及这些分子 在子孢子中识别。我们还将研究这种激活剂的信号转导机制。 导致胞吐的级联反应。(Ii)宿主肝细胞迁移诱导肝细胞释放 使肝细胞易受疟原虫感染的生长因子(HGF)。我们将调查 肝细胞生长因子介导的肝细胞感染易感性的机制，包括细胞骨架 寄生虫空泡的重排、酸化、胆固醇需求和肝细胞 抑制细胞凋亡。 这项研究的结果将有助于理解分子和细胞机制。 介导宿主疟疾发展的第一步：肝细胞感染。人物刻画 感染所需的新型疟原虫和肝细胞因子作为新的 疾病控制的目标。

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 activatory 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 are required for infection hold significant potential as novel targets for disease control.