PLASMODIUM SPOROZOITE INVASION OF TARGET CELLS

这项建议的长期目标是澄清 疟原虫子孢子定位和附着的机制 它们在哺乳动物和蚊子宿主中的靶细胞。少校 子孢子表面蛋白、环子孢子蛋白(CS， 参与两种宿主的靶细胞识别。以前的工作有 研究表明，CS与肝脏硫酸乙酰肝素蛋白多糖(HSPGs)结合 这种结合在肝细胞入侵过程中起作用。到目前为止， 参与唾液腺识别的分子事件尚未被 特征，尽管我们有证据表明CS参与了这一过程 进程。这一进程的具体目标是：1)界定 CS亲和结合所需HSPG的结构要求 II-+区结合蛋白的纯化及鉴定 糖胺多糖(GAG)链。此外，使用新开发的 使我们能够跟踪循环中的子孢子的化验。2)至 确定与CS结合的CS的结构性质 利用合成肽作为竞争对手的蚊子唾液腺 CS的抑制剂与腺体结合并确定是否存在差异 在CS的唾液腺结合区负责 鸡疟原虫经库蚊传播的研究 而不是按蚊。3)通过表达克隆，分离出 并鉴定了CS的唾液腺受体。 我们提出的工作对新药的开发具有重要意义 疟疾的治疗方法和转基因技术的研究现状 蚊子在病媒控制计划中。例如，关于 与CS结合的HSPG Gag链的结构特性可能导致 抑制子孢子定位的药物研究进展 肝脏。此外，对结构属性的了解 参与唾液腺侵袭的受体和配体可能被使用 产生对感染具有抵抗力的转基因蚊子 疟原虫。

The long-term objectives of this proposal are to elucidate the mechanisms by which Plasmodium sporozoites localize to and attach to their target cells in both mammalian and mosquito hosts. The major sporozoite surface protein, the circumsporozoite protein (CS, participates in target cell recognition in both hosts. Previous work has shown that CS binds to hepatic heparan sulfate proteoglycans (HSPGs) and that this binding functions during hepatocyte invasion. To date, the molecular events involved in salivary gland recognition have not been characterize, although we have evidence that CS participates in this process. The specific aims of this process are: 1) To define the structural requirements of HSPGs required for CS binding by affinity purification and characterization of region II-plus binding glycosaminoglycan (GAG) chains. In addition, using newly developed assays that enable us to follow sporozoites from the circulation. 2) To determine the structural properties of CS responsible for binding to mosquito salivary glands by using synthetic peptides as competitive inhibitors of CS binding to glands and to determine whether differences in the salivary gland binding region of CS is responsible for the transmission of the avian malaria parasite P. gallinaceum by Culicine rather than Anophelene mosquitos. 3) By expression cloning, to isolate and characterize the salivary gland receptor for CS. The work we propose is of relevance to the development of new drug therapies for malaria and the current interest in the use of transgenic mosquitos in vector control programs. For example, knowledge of the structural properties of HSPG GAG chains which bind to CS may lead to the development of drugs which could inhibit sporozoite localization to the liver. In addition, knowledge of the structural properties of receptors and ligands involved in salivary gland invasion could be used to generate transgenic mosquitos refractory to infection with Plasmodium.