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

项目摘要 恶性疟原虫是导致严重疟疾的主要原因，包括脑型疟疾和严重疟疾。 疟疾性贫血疟原虫变体表面抗原（VSAs）是展示在疟原虫表面的寄生虫蛋白质， 受感染红细胞，通过结合宿主内皮受体促进细胞粘附和隔离 脉管系统VSAs在发病机制中起着关键作用，并且与特异性结合的VSAs亚类的表达与VSAs的表达相关。 宿主受体与严重疟疾有关。然而，从轻度到重度疾病的进展， 包括对特定的严重疾病综合征，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重要的， 研制出一种对抗严重疟疾的疫苗。恶性疟原虫红细胞膜蛋白-1 抗原（PfEMP 1）是最充分表征的VSA家族。var基因家族编码PfEMP 1， 每个寄生虫基因组估计有40-60个var基因。VSA如PfEMP 1与宿主内皮受体结合， 包括细胞间粘附分子-1（ICAM-1）、CD 36和内皮蛋白C受体（EPCR），从而 阻止受感染红细胞的免疫清除。在蛋白质水平上鉴定PfEMP 1 s已被证明是 由于缺乏序列数据来鉴定临床感染中特定PfEMP 1的特异性肽而受阻。 感染红细胞表面PfEMP 1的RNA测序和随后的蛋白质组学分析 从相同的临床感染，使表达的评估在基因和蛋白质水平，以确定 PfEMP 1对脑型疟疾和严重疟疾性贫血具有特异性。使用来自一项病例对照研究的样本， 西非马里的一项研究将严重疟疾病例与对照组的无并发症疟疾病例进行了比较， 候选人将确定PfEMP 1在基因（Aim 1）和蛋白质水平（Aim）表达的关联 2）。鉴定特异于严重疟疾性贫血和脑型疟疾的PfEMP 1将有助于阐明 严重疾病的发病机制，并为研究提供信息，以检测从临床中确定的PfEMP 1免疫力缺口 感染.这项工作将为候选人提供转录组学，蛋白质组学， 和生物信息学，这将为她作为一个世纪流行病学家和独立的学术生涯做好准备 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.