Glycobiology of the Malaria Parasite

描述：疟疾仍然是世界大部分地区的主要健康问题 迫切需要开发新药或疫苗。疟疾 在流行地区，大多数<3-4岁的儿童有发生严重 疟疾，而成年人已获得对临床疾病的抵抗力。最近 研究已经鉴定了P的糖基磷脂酰肌醇（GPI）锚。 恶性疟原虫毒素与疟疾病理学有关。寄生虫GPIs发挥 通过传递导致炎症表达的信号产生毒性作用 细胞因子和细胞粘附分子，它们启动了 发病机制由于GPIs是致病因子， 成人必须与抗GPIs的抗体反应显著相关。我们 最近发现，肯尼亚西部的成年人体内寄生虫含量很高， GPI特异性抗体，而易感儿童和以前没有的人 暴露于疟疾寄生虫的人缺乏这种抗体反应;抗GPI 抗体应答与疾病保护相关。因此了解 的结构，生物活性和免疫学特性， 寄生虫GPIs可能为开发新的 治疗剂或疫苗以预防感染以及发病机制。在这 我们建议研究的应用：（1）研究自然引发的水平 抗GPI抗体在不同疟疾流行地区的人和 病例对照研究。2)化学合成GPIs的活性部分， 总GPI结构。(2)GPIs诱导炎症反应的研究 在巨噬细胞和实验动物中的反应，并研究 GPIs的抗原性。3)评估GPIs的生物学精氨酸诱导特性 在巨噬细胞和实验动物中，以及它们结合抗GPI的能力 免疫人群血清中的抗体。(4)用GPIs免疫动物， 抗GPI多克隆和单克隆抗体。研究抗血清或纯化 中和GPIs的精氨酸诱导特性的抗体， 研究抗GPI抗体提供抗GPI抗体保护的能力。 疟疾发病机制5)Toll样受体介导诱导的研究GPIs TNF-α在巨噬细胞中的表达6)研究GPI生物合成的抑制， 合成的GPI中间体和糖基转移酶抑制剂。的 长期目标是研究寄生虫GPIs在宿主中的作用， 相互作用，并利用GPI结构的发展， 抗疟疾药物和疫苗。

DESCRIPTION: Malaria is still a major health problem in most parts of the world and development of novel drugs or a vaccine is urgently needed. In malaria endemic areas, most children <3-4 years have a risk of developing severe malaria, whereas adults have acquired resistance to clinical disease. Recent studies have identified glycosyiphosphatidylinositol (GPI) anchors of P. falciparum as the toxins involved in malaria pathology. Parasite GPIs exert toxic effects by transducing signals leading to the expression of inflammatory cytokines and cell adhesion molecules, which initiate the process of pathogenesis. Since GPIs are pathogemcity factors the acquired immunity in adults must be related significantly to antibody response against GPIs. We recently found that adults in Western Kenya have high levels of parasite GPI-specific antibodies, whereas susceptible children and people not previously exposed to malaria parasite lack such an antibody response; the anti-GPI antibody response correlated with disease protection. Therefore, understanding of the structures, biologic activity, and immunologic properties of the parasite GPIs is likely to offer strategies for the development of novel therapeutics or a vaccine to prevent infection as well as pathogenesis. In this application we propose to study: (1) Study the levels of naturally elicited anti-GPI antibodies in people from different malaria endemic regions and in defined case control studies. 2) Chemically synthesize active parts of GPIs and total GPI structures. (2) Study the GPIs for inductionof proinflammatory responses in macrophages and in experimental animals, and investigate the antigenicity of GPIs. 3) Assess biological cytokine-inducing property of GPIs in macrophages and in experimental animals and their ability to bind anti-GPI antibodies in sera of immune people. (4) Immunize animals with GPIs to produce anti-GPI polyclonal and monoclonal antibodies. Study anti-sera or purified antibodies for neutralization of cytokine-inducing property of GPIs and investigate the ability of ant-GPI antibodies in providing protection against malaria pathogenesis. 5) Study GPIs for Toll-like receptor-mediated induction of TNF-a in macrophages. 6) Study inhibition of GPI biosynthesis using synthetic GPI intermediates and inhibitors of glycosyltransferases. The long-term objectives are to study the role of parasite GPIs in host interactions, and to exploit GPI structures for the development of anti-malarial drugs and a vaccine.