Identification of parasite erythrocyte membrane antigens specific to cerebral malaria and severe malarial anemia pathogenesis

项目总结 恶性疟原虫是导致严重疟疾的主要原因，包括脑型疟疾和重型疟疾。 疟疾贫血。疟疾寄生虫变异体表面抗原(VSA)是一种显示在表面的寄生虫蛋白 通过与宿主中的内皮受体结合，促进细胞黏附和隔离 脉管系统。VSA在发病机制中起着关键作用，VSA亚类的表达与特异性 宿主受体与严重疟疾有关。然而，从轻度疾病到严重疾病的进展， 包括对特定的重症综合征，目前还没有完全了解。确定哪种疟疾 寄生虫蛋白在特定严重疟疾综合征的发展中是至关重要的 开发一种针对严重疟疾的疫苗。恶性疟原虫红细胞膜蛋白-1 抗原(PfEMP1)是最具特征性的VSA家族。Var基因家族编码PfEMP1，具有 估计每个寄生虫基因组有40-60个var基因。PfEMP1等VSA与宿主内皮细胞受体结合， 包括细胞间黏附分子-1(ICAM-1)、CD36和内皮蛋白C受体(EPCR)，从而 阻止受感染红细胞的免疫清除。已在蛋白质水平鉴定PfEMP1 由于缺乏序列数据来识别临床感染中特定PfEMP1的特异性多肽，这一工作受到阻碍。 感染红细胞表面PfEMP1的RNA测序及蛋白质组学研究 能够在基因和蛋白质水平上对表达进行评估以识别 针对脑型疟疾和严重疟疾贫血的PfEMP1。使用来自一项病例对照研究的样本 西非马里将严重疟疾病例与与简单疟疾病例相匹配的对照组进行了比较， 候选人将确定PfEMP1在基因(AIM 1)和蛋白质水平(AIM)的表达之间的关联 2)。识别严重疟疾贫血和脑型疟疾特异的PfEMP1将有助于揭示 严重疾病的发病机制和检测来自临床的PfEMP1免疫缺陷的信息研究 感染。这项工作将为应聘者提供转录组学、蛋白质组学、 和生物信息学，这将使她为成为21世纪流行病学家和独立学者的职业生涯做好准备 研究员。

PROJECT SUMMARY Plasmodium falciparum is primarily responsible for severe malaria, including cerebral malaria and severe malarial anemia. Malaria parasite variant surface antigens (VSAs) are parasite proteins displayed on the surface of infected erythrocytes, facilitating cytoadhesion and sequestration by binding endothelial receptors in the host vasculature. VSAs play a critical role in pathogenesis, and the expression of VSAs subclasses that bind specific host receptors has been associated with severe malaria. However, the progression from mild to severe disease, including to the particular severe disease syndrome, is not completely understood. Identifying which malaria parasite proteins are important in the development of specific severe malarial syndromes will be crucial to develop a vaccine against severe malarial disease. Plasmodium falciparum erythrocyte membrane protein-1 antigens (PfEMP1s) are the most well-characterized VSA family. The var gene family encodes PfEMP1s, with an estimated 40-60 var genes per parasite genome. VSAs such as PfEMP1 bind to host endothelial receptors, including intercellular adhesion molecule-1 (ICAM-1), CD36, and endothelial protein C receptor (EPCR), thereby preventing immune clearance of infected erythrocytes. Identification of PfEMP1s at the protein level has been hindered by the lack of sequence data to identify peptides specific to particular PfEMP1s in clinical infections. RNA sequencing and subsequent proteomic profiling of the PfEMP1s on the surface of infected erythrocytes from the same clinical infection enables an evaluation of expression at both the gene and protein level to identify PfEMP1s specific to cerebral malaria and severe malarial anemia. Using samples from a case-control study in Mali, West Africa that compared cases of severe malaria to matched controls with uncomplicated malaria, the candidate will determine the association of the expression of PfEMP1s at the gene (Aim 1) and protein level (Aim 2). Identification of the PfEMP1s specific to severe malarial anemia and to cerebral malaria will shed light on the pathogenesis of severe disease and inform studies to detect gaps in immunity to PfEMP1s identified from clinical infections. This work will provide the candidate with valuable skills in the fields of transcriptomics, proteomics, and bioinformatics that will prepare her for a career as a 21st century epidemiologist and independent academic researcher.