New molecules in malaria sporozoite-hepatocyte infection

疟原虫子孢子在感染最后一个肝细胞之前迁移通过宿主的几个细胞。我们 初步研究表明，这种迁移对于疟疾的建立至关重要，因为：（i）它 激活子孢子，使其有能力侵入肝细胞;（ii）激活邻近的 肝细胞使其易受子孢子感染。 我们计划确定寄生虫和宿主细胞的机制和分子参与这两个关键方面 感染(i)在通过宿主细胞的迁移过程中，子孢子接触肝细胞的胞质溶胶。 引发子孢子中的胞吐作用，这是肝细胞感染所必需的。使用肝细胞提取物， 将识别激活子孢子进行感染的分子以及这些分子的受体， 在子孢子中识别。我们还将研究这种激活的信号转导机制， 级联导致胞吐作用。(ii)通过宿主肝细胞的迁移诱导肝细胞的释放 生长因子（HGF），使肝细胞对疟原虫感染敏感。我们将调查 HGF介导的肝细胞感染易感性的潜在机制，包括细胞骨架 重组，寄生虫空泡酸化，胆固醇需求和肝细胞 凋亡抑制 本研究的结果将有助于理解分子和细胞机制 介导宿主中疟疾发展的第一步：肝细胞的感染。表征 感染所需的新型疟原虫和肝细胞因子具有作为新型 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.