New molecules in malaria sporozoite-hepatocyte infection

疟疾子孢子-肝细胞感染的新分子

• 批准号: 6678501
• 负责人: ANA RODRIGUEZ
• 金额: $ 21.11万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6678501
• 关键词: Plasmodium; apical membrane; apoptosis; biological signal transduction; cell line; cholesterol; cytoskeleton; exocytosis; hepatocyte growth factor; host organism interaction; immunoprecipitation; liver cells; malaria; parasite infection mechanism; spores; vesicle /vacuole

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.

描述（由申请方提供）：疟原虫子孢子在感染最终肝细胞之前迁移通过宿主中的几个细胞。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，使它们能够侵入肝细胞;（ii）它激活邻近的肝细胞，使它们对子孢子感染敏感。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的感染。(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。这触发子孢子中的胞吐作用，这是肝细胞感染所需的。使用肝细胞提取物，我们将确定激活子孢子感染的分子和这些分子在子孢子中识别的受体。我们还将研究导致胞吐作用的这种激活级联的信号转导机制。(ii)通过宿主肝细胞的迁移诱导肝细胞生长因子（HGF）的释放，使肝细胞对疟原虫感染易感。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、寄生虫液泡酸化、胆固醇需求和肝细胞凋亡抑制。 这项研究的结果将有助于了解介导宿主疟疾发展第一步的分子和细胞机制：肝细胞感染。新的疟原虫和肝细胞因子的感染所需的表征具有显着的潜力作为新的疾病控制的目标。