Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Brigham and Women's Hospital, Boston, MA.
J Exp Med. 2021 Mar 1;218(3). doi: 10.1084/jem.20201266.
Cerebral malaria (CM) is caused by the binding of Plasmodium falciparum-infected erythrocytes (IEs) to the brain microvasculature, leading to inflammation, vessel occlusion, and cerebral swelling. We have previously linked dual intercellular adhesion molecule-1 (ICAM-1)- and endothelial protein C receptor (EPCR)-binding P. falciparum parasites to these symptoms, but the mechanism driving the pathogenesis has not been identified. Here, we used a 3D spheroid model of the blood-brain barrier (BBB) to determine unexpected new features of IEs expressing the dual-receptor binding PfEMP1 parasite proteins. Analysis of multiple parasite lines shows that IEs are taken up by brain endothelial cells in an ICAM-1-dependent manner, resulting in breakdown of the BBB and swelling of the endothelial cells. Via ex vivo analysis of postmortem tissue samples from CM patients, we confirmed the presence of parasites within brain endothelial cells. Importantly, this discovery points to parasite ingress into the brain endothelium as a contributing factor to the pathology of human CM.
脑型疟疾（CM）是由感染疟原虫的红细胞（IEs）与脑微血管结合引起的，导致炎症、血管阻塞和脑肿胀。我们之前已经将双重细胞间黏附分子-1（ICAM-1）和内皮蛋白 C 受体（EPCR）结合的疟原虫寄生虫与这些症状联系起来，但导致发病机制的机制尚未确定。在这里，我们使用血脑屏障（BBB）的 3D 球体模型来确定表达双重受体结合 PfEMP1 寄生虫蛋白的 IEs 的意外新特征。对多个寄生虫系的分析表明，IEs 通过 ICAM-1 依赖性方式被脑内皮细胞摄取，导致 BBB 破裂和内皮细胞肿胀。通过对 CM 患者死后组织样本的离体分析，我们证实了脑内皮细胞内寄生虫的存在。重要的是，这一发现表明寄生虫进入脑内皮细胞是导致人类 CM 病理学的一个因素。
