Common virulence gene expression in naive and severe malaria cases

Sequestration of Plasmodium falciparum-infected erythrocytes to host endothelium through the parasite-derived PfEMP1 adhesion proteins, is central to the development of malaria path-ogenesis. PfEMP1 proteins have diversified and expanded to encompass many sequence variants conferring the same array of human endothelial receptor binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32 infected travelers returning to Germany. Patients were categorized into either malaria naive (n=15) or pre-exposed (n=17), and into severe (n=8) or non-severe (n=24) cases. Expression analysis of PfEMP1-encoding var genes showed that severe malaria was associated with expression of PfEMP1 containing the endothelial protein C receptor (EPCR)-binding CIDRα1 domain, whereas CD36-binding PfEMP1 was linked to non-severe malaria outcomes. In addition, gene expression-guided determination of parasite age, suggested that circulating parasites from non-severe malaria patients were older than parasites from severe malaria patients. First-time infected patients were also more likely to develop severe symptoms and tended to be infected for a longer pe-riod, which thus appeared to select for parasites with more sequestration-efficiency and therefore more pathogenic PfEMP1 variants.