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

The virulence of Plasmodium falciparum is closely linked to P. falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by the 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 cassette (DC8 and DC13)-containing var genes have been associated with severe malaria, direct 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 analysed parasite and clinical data from 966 Kenyan children with non-severe malaria and severe malaria syndromes collected over 18 years in Kilifi, Kenya. Var gene transcription was profiled using DBL-tag sequencing (n=898), RT-qPCR (n=768), and DBL-tag-based prediction tools. We show that parasites expressing group A or DC8 var genes were associated with impaired consciousness (IC), while rosetting was associated with respiratory distress (RD) and severe malarial anaemia (SMA), but not IC. Variant expression was more homogeneous in SMA than IC or RD. These findings suggest that IC, RD and SMA reflect distinct underlying parasite virulence strategies: sequestration, rosetting associated parasite virulence, and chronicity of infection respectively. In conclusion, this analysis provides the most comprehensive characterisation of P. falciparum var gene expression across the major severe malaria syndromes to date and highlights the possibility of syndrome-specific parasite virulence mechanisms that may inform the development of targeted therapeutic interventions