Plasmodium Sporozoites Motility and Cell Invasion

疟原虫子孢子运动和细胞侵袭

• 批准号: 6418515
• 负责人: ALI A SULTAN
• 金额: $ 32.36万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6418515
• 关键词: Coccidia; Plasmodium berghei; cell motility; gene targeting; genetic screening; host organism interaction; immunoprecipitation; intermolecular interaction; laboratory mouse; malaria; mass spectrometry; membrane proteins; molecular genetics; parasite infection mechanism; parasitism; pathologic process; polymerase chain reaction; protein binding; protein structure function; radioassay; spores; thrombospondins; yeast two hybrid system

DESCRIPTION: (provided by the applicant): Malaria infection is initiated when Plasmodium sporozoites, which are injected by Anopheles mosquitoes, invade hepatocytes of the vertebrate host. Plasmodium sporozoites actively invade host cells, and display gliding motility, both actions being powered by parasite microfilaments. The molecular mechanisms involved in motility and invasion are largely unknown but are thought to be related. We have shown previously that a sporozoite surface molecule, the thrombospondin-related anonymous protein (TRAP), is required for sporozoite gliding motility and infection of hepatocytes. The objective of this proposal is to apply biochemical, cell biological and genetic approaches to elucidate the functional role of TRAP in host cell invasion by Plasmodium berghei. Our working hypothesis is that TRAP acts as a molecular link between the parasite cortical microfilaments and the host cell surface thereby, enabling the parasite to move and invade its target cell. TRAP, which is a typical type-1 transmembrane protein, has a long extracellular region, which contains two adhesive domains, and a short cytoplasmic tail. Our preliminary results indicate that TRAP may mediate target cell invasion by engaging with host cell surface proteins through its adhesive domains. In addition, the cytoplasmic tail of TRAP may interact with components of the sporozoite cortical microfilament system, possibly a motor protein such as myosin. The goal of this proposal is to identify and characterize host and parasite proteins that interact with the adhesive domains as well as the cytoplasmic tail of TRAP. Identification of TRAP-interacting molecules in the parasite or the host cell will further our understanding of sporozoite motility and invasion and will provide the basis for developing new malaria vaccines and chemotherapeutic agents.

描述：（由申请人提供）：疟疾感染是在 由蚊子蚊子注射的疟原虫孢子菌入侵 脊椎动物宿主的肝细胞。疟原虫孢子菌主动入侵宿主 细胞，并显示滑行运动，这两个动作都由寄生虫提供动力 微丝。参与运动和侵袭的分子机制是 在很大程度上未知，但被认为是相关的。我们之前已经证明了 Sporozoite表面分子，与血小板素相关的匿名蛋白 （陷阱），需要Sporozoite滑行运动和感染 肝细胞。该建议的目的是应用生化的细胞 生物学和遗传方法阐明陷阱在 骨berghei的宿主细胞侵袭。 我们的工作假设是，陷阱是 寄生虫皮层微丝和宿主细胞表面，因此 移动并侵入其目标细胞的寄生虫。陷阱，这是一个典型的 1型跨膜蛋白具有长的细胞外区域，其中包含 两个粘合域和一个短的细胞质尾巴。我们的初步结果 表明陷阱可以通过与宿主细胞接合来介导目标细胞侵袭 表面蛋白通过其粘合剂结构域。另外，细胞质 陷阱的尾巴可能与孢子岩皮质的成分相互作用 微丝系统，可能是运动蛋白，例如肌球蛋白。 该提议的目的是识别和表征宿主和寄生虫 与粘合剂结构域以及细胞质相互作用的蛋白质 陷阱的尾巴。在寄生虫或 宿主细胞将进一步了解孢子岩运动性和 入侵，将为开发新的疟疾疫苗和 化学治疗剂。