The clinical outcome of Plasmodium falciparum
infections ranges from asymptomatic
parasitemia to severe
malaria syndromes associated with high mortality. The virulence of P. falciparum
infections is associated with the type of P. falciparum erythrocyte membrane
protein 1 (PfEMP1) expressed on the surface of infected erythrocytes to anchor these to the vascular lining. Although var2csa, the var gene encoding the PfEMP1 associated with placental
malaria, was discovered in 2003, the identification of the var/PfEMP1 variants associated with severe
malaria in children has remained elusive. To identify var/PfEMP1 variants associated with severe disease outcome, we compared var transcript levels in parasites from 88 children with severe
malaria and 40 children admitted to the hospital with uncomplicated
malaria. Transcript analysis was performed by RT-quantitative PCR using a set of 42 primer pairs amplifying var subtype-specific loci covering most var/PfEMP1 subtypes. In addition, we characterized the near-full-length sequence of the most prominently expressed var genes in three patients diagnosed with severe
anemia and/or
cerebral malaria. The combined analysis showed that severe
malaria syndromes, including severe
anemia and
cerebral malaria, are associated with high transcript levels of PfEMP1 domain cassette 8-encoding var genes. Transcript levels of group A var genes, including genes encoding domain cassette 13, were also significantly higher in patients with severe syndromes compared with those with uncomplicated
malaria. This study specifies the var/PfEMP1 types expressed in severe
malaria in children, and thereby provides unique targets for future efforts to prevent and treat severe
malaria infections.