Common virulence gene expression in adult first-time infected malaria patients and severe cases.

Abstract

Sequestration of <i>Plasmodium falciparum</i>(<i>P. falciparum</i>)-infected erythrocytes to host endothelium through the parasite-derived <i>P. falciparum</i> erythrocyte membrane protein 1 (<i>Pf</i>EMP1) adhesion proteins is central to the development of malaria pathogenesis. <i>Pf</i>EMP1 proteins have diversified and expanded to encompass many sequence variants, conferring each parasite a similar array of human endothelial receptor-binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32 <i>P. falciparum-</i>infected adult travellers 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. For differential expression analysis, <i>Pf</i>EMP1-encoding <i>var</i> gene transcripts were de novo assembled from RNA-seq data and, in parallel, <i>var-</i>expressed sequence tags were analyzed and used to predict the encoded domain composition of the transcripts. Both approaches showed in concordance that severe malaria was associated with <i>Pf</i>EMP1 containing the endothelial protein C receptor (EPCR)-binding CIDRα1 domain, whereas CD36-binding <i>Pf</i>EMP1 was linked to non-severe malaria outcomes. First-time infected adults were more likely to develop severe symptoms and tended to be infected for a longer period. Thus, parasites with more pathogenic <i>Pf</i>EMP1 variants are more common in patients with a naive immune status, and/or adverse inflammatory host responses to first infections favor the growth of EPCR-binding parasites.