MOLECULAR ANALYSIS OF ANTIGENIC VARIATION IN MALARIA

疟疾抗原变异的分子分析

• 批准号: 2886910
• 负责人: MARY R GALINSKI
• 金额: $ 32.71万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2886910
• 关键词: DNA; Macaca mulatta; Plasmodium knowlesi; SDS polyacrylamide gel electrophoresis; affinity chromatography; antibody specificity; gene expression; genetic library; genetic recombination; host organism interaction; immunofluorescence technique; immunoprecipitation; laboratory mouse; laboratory rabbit; malaria; molecular cloning; molecular genetics; northern blottings; parasitism; phenotype; polymerase chain reaction; protein sequence; protein structure function; protozoal antigen; western blottings

The long term goal is to understand the phenomenon of Plasmodium antigenic variation, a major factor in the development of chronic malaria blood-stage infections and a determinant of parasite virulence. The proposed studies will be performed using the Plasmodium knowlesi/rheusus monkey model system, in which malaria antigenic variation was first identified. The P. knowlesi variant antigens are high molecular weight, parasite-encoded proteins that are inserted into the infected host erythrocyte membrane and are partially exposed at its surface. These proteins, known as the SICA (schizont infected cell agglutination) antigens, change in size and antigenicity int he course of a blood infection. With the recent cloning of the first variant antigen genes of P. knowlesi (the SICA var genes), which are members of a large multigene family, it is now possible to study the mechanisms of antigenic variation in vivo as well as in-vitro. Previous in-vivo studies using unique, stable cloned populations of P. knowlesi, which express known variant antigen phenotypes, and the rhesus monkey model system have suggested that antigenic variation of the SICA var proteins is induced by variant-specific antibody, is modulated by athe host spleen, and is a factor in the virulence of this parasite. Now with molecular probes in-hand, questions pertaining to tahe molecular mechanisms of gene expression and the immunobiology of antigenic variation can be addressed. Importantly, athe studies that are possible with P. knowlesi will provide information about the process of malaria antigenic variation that may not be generated by direct studies of the predominant human malarias P. falciparum or P. vivax, since there are neither comparable in- vivo models nor in-vitro systems that are easily manipulated and controlled. Thus, the proposed work provides a valuable interspecies comparative model that will in all likelihood continue to generate knowledge that is relevant for and contribute to understanding antigenic variation of human malaria parasites. Although the function of related P. falciparum variant antigens is currently believed to be cytoadherence/sequestration, it is also important to ask what other functions these proteins may have, as neither P. knowlesi nor P. vivax show a comparably marked sequestration as seen in falciparum malaria. Determining the genetic and immunobiological mechanisms involved with switching of malaria variant antigen phenotypes will be of general importance for furthering the knowledge about molecular mechanisms of parasitism in malaria and the P. knowlesi model could provide athe critical clues necessary for deciphering these mechanisms.

长期目标是了解疟原虫抗原的现象 变异是慢性疟疾血期发展的一个主要因素 感染和寄生虫毒力的决定因素。 拟议的研究 将使用诺氏疟原虫/恒河猴模型进行 系统，其中首次鉴定出疟疾抗原变异。 P。 诺氏变异抗原是高分子量、寄生虫编码的 插入受感染宿主红细胞膜的蛋白质和 部分暴露在其表面。 这些蛋白质被称为 SICA （裂殖体感染细胞凝集）抗原、大小和变化 血液感染过程中的抗原性。 随着最近的克隆 诺氏疟原虫的第一个变异抗原基因（SICA var 基因）， 它们是一个大的多基因家族的成员，现在可以研究 体内和体外抗原变异的机制。 之前的体内研究使用了独特、稳定的 P. 诺氏病毒，表达已知的变异抗原表型，以及恒河猴 猴模型系统表明 SICA var 的抗原变异 蛋白质由变体特异性抗体诱导，由宿主调节 脾脏，是这种寄生虫毒力的一个因素。 现在与 分子探针在手，有关分子机制的问题 基因表达和抗原变异的免疫生物学可以是 已解决。 重要的是，诺氏疟原虫可能的研究 将提供有关疟疾抗原变异过程的信息 这可能不是通过对主要人类的直接研究产生的 疟疾 P. falciparum 或 P. vivax，因为两者都没有可比性 易于操作的体内模型或体外系统 受控。 因此，拟议的工作提供了有价值的种间 比较模型很可能会继续产生 与理解抗原相关并有助于理解抗原的知识 人类疟疾寄生虫的变异。 虽然相关P的功能。 目前认为恶性疟原虫变异抗原 细胞粘附/隔离，询问其他什么也很重要 这些蛋白质可能具有的功能，诺氏疟原虫和间日疟原虫均未显示 如恶性疟疾中所见的相对显着的隔离。 确定相关的遗传和免疫生物学机制 疟疾变异抗原表型的转换将具有普遍性 对于加深对分子机制的了解具有重要意义 疟疾中的寄生和诺氏疟原虫模型可以提供关键的 破译这些机制所必需的线索。