MOLECULAR ANALYSIS OF ANTIGENIC VARIATION IN MALARIA

长期目标是了解疟原虫的抗原性现象 变异是慢性疟疾血液期发展的主要因素 感染和寄生虫毒力的决定因素。建议进行的研究 将使用诺氏疟原虫/大风湿猴模型进行实验 系统，在该系统中，首次发现了疟疾抗原变异。通过对P. 诺氏变种抗原是由寄生虫编码的高分子量抗原。 插入受感染的宿主红细胞膜的蛋白质和 部分暴露在它的表面。这些被称为SICA的蛋白质 (裂殖体感染的细胞凝集)抗原，大小变化和 血液感染病程的抗原性。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)中， 它们是一个多基因大家族的成员，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了独特、稳定的P。 表达已知变异抗原表型的诺氏杆菌和恒河猴 猴模型系统提示SICA变种的抗原性变异 蛋白质是由变种特异性抗体诱导的，受宿主的调节 脾，是这种寄生虫毒力的一个因素。现在有了 分子探针在手，与塔河分子机制有关的问题 基因表达和免疫生物学的抗原变异可以 地址。重要的是，诺氏疟原虫可能进行的研究 将提供有关疟疾抗原变异过程的信息 可能不是通过对占主导地位的人类的直接研究而产生的 恶性疟原虫或间日疟原虫，因为在- 无论是活体模型还是体外系统，都很容易操纵和 控制住了。因此，拟议的工作提供了一个有价值的物种间 这种比较模式很可能会继续产生 与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。虽然相关的P. 恶性疟原虫变异抗原目前被认为是 细胞黏附/隔离，同样重要的是要问 正如诺氏疟原虫和间日疟原虫都没有显示的那样，这些蛋白质可能具有功能。 在恶性疟疾中可见的类似显著的隔离。 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是普遍的 加深对血吸虫病分子机制认识的重要性 疟疾中的寄生虫和诺氏疟原虫模型可以提供一个关键的 破译这些机制所需的线索。

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.