MOLECULAR ANALYSIS OF ANTIGENIC VARIATION IN MALARIA

长期目标是了解疟原虫抗原性的现象， 变异是慢性疟疾发展的主要因素 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/风湿病猴模型进行 该系统首次发现了疟疾抗原变异。 假单 Knowlesi变体抗原是高分子量、寄生虫编码的 插入受感染宿主红细胞膜的蛋白质， 部分暴露在其表面。 这些被称为SICA的蛋白质 （抗原感染的细胞凝集）抗原，大小变化和 血液感染过程中的抗原性。 随着最近的克隆 在诺氏疟原虫的第一变体抗原基因（SICA var基因）中， 作为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。 以前的体内研究使用独特的，稳定的克隆群体的P。 knowlesi，其表达已知的变体抗原表型，以及恒河猴， 猴模型系统表明，SICA变异的抗原变异 蛋白质是由变异体特异性抗体诱导的，受宿主的调节， 脾，是这种寄生虫毒力的一个因素。 现在随着 分子探针在手，有关tahe分子机制的问题 基因表达和抗原变异的免疫生物学可以 处理。 重要的是，对诺氏疟原虫的研究是可能的， 将提供有关疟疾抗原变异过程的信息 这可能不是通过直接研究主要的人类 恶性疟原虫或间日疟原虫，因为在- 体内模型或体外系统，易于操作， 控制。 因此，拟议的工作提供了一个有价值的物种间 比较模型，将在所有的可能性继续产生 与理解抗原相关并有助于理解抗原的知识 人类疟原虫的变异。 虽然相关P. 目前认为恶性疟原虫变体抗原 细胞粘附/隔离，也很重要的是要问什么其他 这些蛋白质可能具有的功能，诺氏疟原虫和间日疟原虫都没有显示出来， 一种在恶性疟疾中看到的明显的隔离。 确定参与的遗传和免疫生物学机制 疟疾变异抗原表型的转换通常是 重要的是进一步了解分子机制， 疟疾中的寄生虫和P. knowlesi模型可以提供关键的 破译这些机制的必要线索。

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.