Gill Jasmita, Sharma Amit
ICMR-National Institute of Malaria Research, New Delhi, India.
ICMR-National Institute of Malaria Research, New Delhi, India; International Centre for Genetic Engineering and Biotechnology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
Infect Genet Evol. 2023 Jun;110:105413. doi: 10.1016/j.meegid.2023.105413. Epub 2023 Feb 10.
Plasmodium parasites responsible for malaria follow a complex life cycle of which half takes place inside the human host. Parasites present diverse antigens at different stages of their life cycle and interact with many surface molecules to attach to and enter host cells. The CIDRα1 domain of Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) in infected erythrocytes adheres to one such vascular receptor endothelial protein C receptor (EPCR). EPCR is implicated in the pathogenesis of severe malaria as preferential binding of CIDRα1 to endothelium results in widespread sequestration of infected erythrocytes leading to endothelium inflammation and severe disease. A single EPCR variant S219G is clinically reported to provide protection from severe malaria. In this work, we have collated all single nucleotide polymorphisms (SNPs) in EPCR from dbSNP. We structurally mapped the SNPs on the three-dimensional complex of EPCR and PfEMP1 CIDRα1. Analysis shows that most EPCR mutations lie on the receptor surface and are non-conservative. Of the 11 mutations in the CIDRα1-interaction region of EPCR, S88P, L96V/I, and R98L/H/P/C are seen with comparably higher occurrences in diverse populations. Our structural analysis details a framework of the interactions between the parasite ligand and host factor EPCR. These structural glimpses provide a blueprint for designing both field-based variant sequencing studies and vaccine development.
引发疟疾的疟原虫遵循复杂的生命周期，其中一半在人类宿主体内进行。疟原虫在其生命周期的不同阶段呈现出多样的抗原，并与许多表面分子相互作用，以附着并进入宿主细胞。感染红细胞中的恶性疟原虫红细胞膜蛋白1（PfEMP1）的CIDRα1结构域会黏附于一种这样的血管受体——内皮蛋白C受体（EPCR）。EPCR与重症疟疾的发病机制有关，因为CIDRα1与内皮细胞的优先结合会导致感染红细胞广泛滞留，进而引发内皮炎症和严重疾病。临床报告称，单一的EPCR变体S219G可预防重症疟疾。在这项研究中，我们整理了来自dbSNP的EPCR中的所有单核苷酸多态性（SNP）。我们在EPCR与PfEMP1 CIDRα1的三维复合物上对这些SNP进行了结构定位。分析表明，大多数EPCR突变位于受体表面，且是非保守性的。在EPCR的CIDRα1相互作用区域的11个突变中，S88P、L96V/I和R98L/H/P/C在不同人群中的出现频率相对较高。我们的结构分析详细阐述了寄生虫配体与宿主因子EPCR之间相互作用的框架。这些结构上的见解为设计基于现场的变体测序研究和疫苗开发提供了蓝图。
