Abstract
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.
Highlights
60 different Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants are encoded by each haploid genome of P. falciparum, allowing this human malaria parasite to undergo antigenic variation and evade the immune system
The number of bound infected erythrocytes (IEs) was observed to significantly increase over time (1 vs. 6 h) for erythrocytes infected by three different lines (HB3VAR03, 3D7 PFD1235w, and BM057) of group A+Cerebral malaria (CM) parasites (Fig. 1 A4 and Table 1), while no significant change was observed for erythrocytes infected by group BUM and CUM (IT4VAR13, HB3VAR21, and HB3VAR34), nor group B/ASM parasites (IT4VAR19 and IT4VAR20; Fig. 1, B4–D4; and Fig. S2)
A comparison of the endothelial responses to adhesion by well-defined parasite lines illustrated the differential effects elicited by group A+CM IEs (ICAM-1– and endothelial protein C receptor (EPCR)-binding) expressing PfEMP1s with a highly conserved intercellular adhesion molecule-1 (ICAM-1)–binding sequence motif (Lennartz et al, 2017), as compared with group BUM (ICAM-1– and CD36-binding or ICAM-1 only) and CUM IEs (ICAM-1–binding), and group B/ASM IEs (EPCR-binding)
Summary
60 different Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants are encoded by each haploid genome of P. falciparum, allowing this human malaria parasite to undergo antigenic variation and evade the immune system. IE receptor adhesion leads to occlusion of the vessels When this occurs in the brain, it can lead to sudden, rapid swelling of the brain, and death can result from respiratory failure due to brain stem herniation (Seydel et al, 2015; Newton et al, 1991; Crawley et al, 1998; Potchen et al, 2018). In the murine Plasmodium chabaudi model of malaria, IEs are observed perivascular to multiple organs, including the brain (Mota et al, 2000). These perivascular parasites were accompanied by gross morphological changes to the endothelial surface with microvilli-like projections and swelling of the endothelial cells (Mota et al, 2000). There is limited information on the presence of P. falciparum–IEs beyond the blood–brain barrier (BBB), with only one postmortem study reporting the presence of IEs within the brain parenchyma (Pongponratn et al, 2003)
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