Plasmodium Sporozoites Motility and Cell Invasion

描述：(申请人提供)：疟疾感染在以下情况下开始 由按蚊注射的疟原虫子孢子入侵 脊椎动物宿主的肝细胞。疟原虫子孢子主动入侵宿主 细胞，并显示滑动运动，这两种活动都是由寄生虫提供动力的 微丝。参与运动和入侵的分子机制是 基本不为人所知，但被认为是相关的。我们以前已经展示了一个 凝血酶原蛋白相关的匿名蛋白--子孢子表面分子 (TRAP)，是子孢子滑动运动和感染 肝细胞。这项提议的目标是将生化、细胞 用生物学和遗传学方法阐明TRAP在细胞周期中的功能作用 伯氏疟原虫侵袭宿主细胞。 我们的工作假设是，TRAP起到了分子连接的作用 寄生的皮质微丝和宿主细胞表面，从而使 寄生虫移动并入侵其目标细胞。陷阱，这是一个典型的 I型跨膜蛋白，有一个很长的胞外区，包含 两个粘连结构域，以及一条短的细胞质尾巴。我们的初步结果 表明Trap可能通过与宿主细胞接触来介导靶细胞侵袭 表面蛋白通过其粘附域。此外，细胞质 捕捉器的尾部可能与子孢子的皮质成分相互作用 微丝系统，可能是一种运动蛋白，如肌球蛋白。 这项提案目标是识别和描述宿主和寄生虫 与粘附区和细胞质相互作用的蛋白质 陷阱的尾巴。寄生虫或寄生虫中陷阱相互作用分子的鉴定 宿主细胞将进一步加深我们对子孢子运动和 并将为开发新的疟疾疫苗和 化疗药物。

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.