Plasmodium Sporozoites Motility and Cell Invasion

描述：（由申请人提供）：疟疾感染开始时， 疟原虫子孢子由按蚊注入体内， 脊椎动物宿主的肝细胞。疟原虫子孢子主动侵入宿主 细胞，并显示滑行运动，这两个行动是由寄生虫 微丝参与运动和侵袭的分子机制是 大部分是未知的，但被认为是相关的。我们之前已经证明， 子孢子表面分子，血小板反应蛋白相关的无名蛋白 （TRAP）是子孢子滑行运动和感染所必需的 肝细胞这项提案的目的是应用生物化学，细胞， 生物学和遗传学方法来阐明TRAP在 伯氏疟原虫侵入宿主细胞。 我们的工作假设是，TRAP作为一个分子之间的联系， 寄生虫皮层微丝和宿主细胞表面，从而使 寄生虫移动并侵入其靶细胞。陷阱，这是一个典型的 1型跨膜蛋白，具有长的胞外区，其含有 两个粘附区和一个短的胞质尾区。我们的初步结果 表明TRAP可能通过与宿主细胞结合介导靶细胞侵袭 表面蛋白通过其粘附结构域。此外，细胞质 TRAP的尾部可能与子孢子皮层的成分相互作用 微丝系统，可能是马达蛋白，如肌球蛋白。 本提案的目标是识别和表征宿主和寄生虫 与粘附结构域以及细胞质相互作用的蛋白质 陷阱的尾巴鉴定寄生虫中的TRAP相互作用分子，或 宿主细胞将进一步加深我们对子孢子运动性的理解， 并将为开发新的疟疾疫苗提供基础， 化疗剂。

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.