Expression of specific var gene subtypes is differentially associated with severe malaria syndromes

The virulence of Plasmodium falciparum is closely linked to P. falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by a diverse var gene family. PfEMP1 mediates parasite immune evasion and vascular adhesion of infected red blood cells, contributing to severe disease. While expression of group A or domain cassettes (DC8 and DC13)-containing var genes have been associated with severe malaria, comparisons between the severe malaria syndromes remain limited. Furthermore, interactions between specific var gene expression and the rosetting phenotype, a known marker of severe malaria, are incompletely understood across severe malaria syndromes. We analyzed parasites and clinical data from 712 Kenyan children with non-severe and severe malaria syndromes collected over 18 years in Kilifi, Kenya. We used RT-qPCR and DBL-tag sequencing to quantify var gene expression. We show that parasites expressing var genes containing the cys2 MFK+REY-motif or encoding DC8 domains were associated with impaired consciousness (IC), while rosetting was associated with respiratory distress (RD) and severe malarial anaemia (SMA), but not IC. These findings demonstrate that distinct PfEMP1 variants are preferentially expressed in specific severe malaria syndromes, highlighting potential targets for variant-specific future therapeutic and diagnostic strategies.